Tricyclic quinoline and quinoxaline derivatives

ABSTRACT

The present invention relates to tricyclic quinoline and quinoxaline derivatives, to a pharmaceutical composition containing such compounds, to their use as modulators, especially agonists or partial agonists, of the 5-HT 2C  receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT 2C  receptor, and to a method for preventing or treating conditions and disorders which respond to the modulation of 5-HT 2C  receptor.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This is a continuation of U.S. Patent Application No. 13/838,788, filedon Mar. 15, 2013, which claims priority to U.S. Provisional PatentApplication No. 61/701,531, filed on Sep. 14, 2012, and U.S. ProvisionalPatent Application No. 61/701,514, filed on Sep. 14, 2012, the entirecontents of all of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to tricyclic quinoline and quinoxalinederivatives, to a pharmaceutical composition containing such compounds,to their use as modulators, especially agonists or partial agonists, ofthe 5-HT_(2C) receptor, their use for preparing a medicament for theprevention or treatment of conditions and disorders which respond to themodulation of 5-HT_(2C) receptor, to a method for preventing or treatingconditions and disorders which respond to the modulation of 5-HT_(2C)receptor, and processes for preparing such compounds and compositions.

BACKGROUND OF THE INVENTION

Diseases, disorders and conditions where 5-HT_(2C) modulation is desiredare for example depression, anxiety, schizophrenia, bipolar disorder,obsessive compulsive disorder, migraine, pain, epilepsy, substanceabuse, eating disorders, obesity, diabetes, erectile dysfunction andothers.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter andlocal hormone, is formed by the hydroxylation and decarboxylation oftryptophan. The greatest concentration is found in the enterochromaffincells of the gastrointestinal tract, the remainder being predominantlypresent in platelets and in the Central Nervous System (CNS). 5-HT isimplicated in a vast array of physiological and pathophysiologicalpathways. In the periphery, it contracts a number of smooth muscles andinduces endothelium-dependent vasodilation. In the CNS, it is believedto be involved in a wide range of functions, including the control ofappetite, mood, anxiety, hallucinations, sleep, vomiting and painperception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HTis exerted upon its interaction with specific (serotonergic) neurons.Seven types of 5-HT receptors have been identified: 5-HT₁ (with subtypes5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(1E) and 5-HT_(1F)), 5-HT₂ (withsubtypes 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)), 5-HT₃, 5-HT₄, 5-HT₅ (withsubtypes 5-HT_(5A) and 5-HT_(5B)), 5-HT₆ and 5-HT₇. Most of thesereceptors are coupled to G-proteins that affect the activities ofadenylate cyclase or phospholipase Cγ.

Alterations in the activity of multiple neurotransmitter receptorsystems (dopamine, serotonin, glutamate, GABA, acetylcholine) have beenimplicated in the manifestation of the symptoms of schizophrenia. Themost widely accepted “Dopamine Hypothesis of Schizophrenia” in itssimplest form states that the positive symptoms of this pathology relateto a functional hyperactivity of the mesolimbic dopaminergic system,while the negative and cognitive aspects can be traced to a functionalhypoactivity of the mesocortical dopaminergic projections. Atypicalantipsychotics block the mesolimbic dopaminergic neurotransmission,thereby controlling positive symptoms, with little or no effect on thenigrostriatal system, leading to less induction of extrapyramidal sideeffects (EPS).

Primary negative and cognitive symptoms of schizophrenia reflect adysfunction of the frontal cortex (“hypofrontality”), which is thoughtto be induced by a decreased tone in the mesocortical dopaminergicprojection field [Davis K L, Kahn R S, Ko G and Davidson M (1991).Dopamine in schizophrenia: a review and re-conceptualization. Am JPsychiatry 148: 1474-86. Weinberger D R and Berman K F (1996).Prefrontal function in schizophrenia: confounds and controversies.Philos Trans R Soc Lond B Biol Sci 351: 1495-503]. Agents thatselectively enhance dopamine levels in the cortex have the potential toaddress the negative symptoms of this disorder. Atypical antipsychoticslack robust efficacy against negative and cognitive components of theschizophrenic syndrome.

The schizophrenic symptomatology is further complicated by theoccurrence of drug-induced so-called secondary negative symptoms andcognitive impairment, which are difficult to distinguish from primarynegative and cognitive symptoms [Remington G and Kapur S (2000).Atypical antipsychotics: are some more atypical than others?Psychopharmacol 148: 3-15]. The occurrence of secondary negativesymptoms not only limits therapeutic efficacy but also, together withthese side effects, negatively affects patient compliance.

It may thus be hypothesized that a novel mechanistic approach thatblocks dopaminergic neurotransmission in the limbic system but does notaffect the striatal and pituitary projection fields, and stimulatesfrontocortical projection fields, would provide an efficacious treatmentfor all parts of the schizophrenic pathology, including its positive,negative and cognitive symptoms. Moreover, a selective compound that issubstantially free of the ancillary pharmacology that characterizescurrent agents would be expected to avoid a variety of off-target sideeffects that plague current treatments such as extrapyramidal sideeffects (EPS) and weight gain.

The 5-HT_(2C) receptor, previously named 5-HT1C, is a G-protein-coupledreceptor, which couples to multiple cellular effector systems includingthe phospholipase C, A and D pathways. It is found primarily in thebrain and its distribution is particularly high in the plexuschoroideus, where it is assumed to control cerebrospinal fluidproduction [Kaufman M J, Hirata F (1996) Cyclic GMP inhibitsphosphoinositide turnover in choroid plexus: evidence for interactionsbetween second messengers concurrently triggered by 5-HT_(2C) receptors.Neurosci Lett 206:153-156]. Very high levels were also found in theretrosplenial, piriform and entorhinal cortex, anterior olfactorynucleus, lateral septal nucleus, subthalamic nucleus, amygdala,subiculum and ventral part of CA3, lateral habenula, substantia nigrapars compacta, several brainstem nuclei and the whole grey matter of thespinal cord [Pompeiano M, Palacios J M, Mengod G (1994). Distribution ofthe serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT_(2A)and 5-HT_(2C) receptors. Brain Res Mol Brain Res 23:163-178]. Acomparison of the distribution of 5-HT_(2C) mRNA with that of 5-HT_(2C)protein in monkey and human brains has revealed both pre- andpostsynaptic localization [Lopez-Gimenez J F, Mengod G, Palacios J M,Vilaro M T (2001) Regional distribution and cellular localization of5-HT_(2C) receptor mRNA in monkey brain: comparison with [³H]mesulerginebinding sites and choline acetyltransferase mRNA. Synapse 42:12-26].

It is anticipated that modulation of the 5-HT_(2C) receptor will improvedisorders such as depression, anxiety, schizophrenia, cognitive deficitsof schizophrenia, obsessive compulsive disorder, bipolar disorder,migraine, epilepsy, substance abuse, eating disorders, obesity,diabetes, sexual dysfunction/erectile dysfunction, sleep disorders,psoriasis, Parkinson's disease, pain conditions and disorders, andspinal cord injury, smoking cessation, ocular hypertension andAlzheimer's disease. Modulators of the 5-HT_(2C) receptor are also shownto be useful in the modulation of bladder function, including theprevention or treatment of urinary incontinence.

There is an ongoing need for providing compounds having high affinityand selectivity for the 5-HT_(2c) receptor. In particular the compoundsshould have low affinity to adrenergic receptors, such as theα₁-adrenergic receptor, histamine receptors, such as the H₁-receptor,and dopaminergic receptors, such as the D₂-receptor, in order to avoidor reduce side effects associated with modulation of these receptors,such as postural hypotension, reflex tachycardia, potentiation of theantihypertensive effect of prazosin, terazosin, doxazosin and labetalolor dizziness associated with the blockade of the α₁-adrenergic receptor,weight gain, sedation, drowsiness or potentiation of central depressantdrugs associated with the blockade of the H₁-receptor, or extrapyramidalmovement disorder, such as dystonia, parkinsonism, akathisia, tardivedyskinesia or rabbit syndrome, or endocrine effects, such as prolactinelevation (galactorrhea, gynecomastia, mentstrual changes, sexualdysfunction in males), associated with the blockade of the D₂-receptor.

The present invention provides compounds which have an affinity for the5-HT_(2C), thus allowing the treatment of disorders related to oraffected by the 5-HT_(2C) receptor.

SUMMARY OF THE INVENTION

The invention is directed to tricyclic qunioline and quinoxalinederivatives, compositions comprising such compounds, their use asmodulators, especially agonists or partial agonists, of the 5-HT_(2C)receptor, their use for preparing a medicament for the prevention ortreatment of conditions and disorders which respond to the modulation of5-HT_(2C) receptor, to a method for preventing or treating conditionsand disorders which respond to the modulation of 5-HT_(2C) receptor, andprocesses for preparing such compounds and compositions.

In one aspect, the present invention relates to compounds of the formula(I):

wherein

-   G is (CR^(3a)R^(3b))_(n);-   X is NR⁶ or CR⁷R⁸;-   R¹ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, phenyl, phenyl-C₁-C₂-alkyl and    a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated    or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4    heteroatoms or heteroatom groups independently selected from N, O,    S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups    as ring members, where the cyclic moieties in the three    last-mentioned radicals may be substituted with one or more    substituents R¹¹;-   each R² is independently selected from the group consisting of    cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹¹;-   R^(3a) and R^(3b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    -   NR^(12a)C(O)R¹⁰, —C(O)R¹⁰, —CH₂NR^(12a)R^(12b),        C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy,        phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy        and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring containing 1, 2, 3 or        4 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the        cyclic moieties in the six last-mentioned radicals may be        substituted with one or more substituents R¹¹;-   R^(4a) and R^(4b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl,    -   NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰,        —C(═O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy,        fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl,        phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or        8-membered saturated, partially unsaturated or maximally        unsaturated ring containing 1, 2, 3 or 4 heteroatoms or        heteroatom groups independently selected from N, O, S, NO, SO,        SO₂, C═O and C═S as ring members, where the cyclic moieties in        the six last-mentioned radicals may be substituted with one or        more substituents R¹¹; or R^(4a) and R^(4b) form together a        group ═O or ═S;-   R^(5a) and R^(5b), independently of each other, are selected from    the group consisting of hydrogen, deuterium, halogen, cyano, nitro,    hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹¹; or    -   R^(5a) and R^(5b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹; or R^(5a) and R⁶, together with the atoms they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated heterocyclic ring, where        the ring may further contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹¹; or    -   R^(5a) and R⁷, together with the carbon atoms they are bound to,        form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹;-   R⁶ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl    -C₁-C₄-alkyl, fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, —SO₂R¹⁰, phenyl,    phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,    partially unsaturated or maximally unsaturated heterocyclic ring    containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO and SO₂ and optionally    also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic    moieties in the three last-mentioned radicals may be substituted    with one or more substituents R¹¹;-   R⁷ and R⁸, independently of each other, are selected from the group    consisting of deuterium, halogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    -   NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),        C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy,        phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy        and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring containing 1, 2, 3 or        4 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the        cyclic moieties in the six last-mentioned radicals may be        substituted with one or more substituents R¹¹; or    -   R⁷ and R⁸, together with the carbon atom they are bound to, form        a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹;-   each R⁹ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄ alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    —NR^(12a)C(O) R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹¹; or    -   two radicals R⁹ bound on neighbouring carbon atoms, together        with the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-,        7- or 8-membered partially unsaturated or maximally unsaturated        ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹¹;-   each R¹⁰ is independently selected from the group consisting of    hydrogen, cyano, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally unsaturated    ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the five last-mentioned    radicals may be substituted with one or more substituents R¹¹;-   each R¹¹ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —COOH, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,    C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl,    SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy and fluorinated    C₁-C₆-alkylcarbonyloxy;-   R^(12a) and R^(12b), independently of each other and independently    of each occurrence, are selected from the group consisting of    hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated    C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties    in the two last-mentioned radicals may carry 1, 2 or 3 substituents    selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,    -   if R^(12a) and R^(12b) are bound to the same nitrogen atom,        together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7-        or 8-membered saturated, partially unsaturated or maximally        unsaturated heterocyclic ring, where the ring may further        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated        C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;-   a is 0, 1 or 2;-   b is 0, 1, 2 or 3; and-   n is 1 or 2;    and the N-oxides, tautomeric forms, stereoisomers and    pharmaceutically acceptable salts thereof, and the compound of the    general formula I, wherein at least one of the atoms has been    replaced by its stable, non-radioactive isotope.

In another aspect, the invention relates to compounds of formula I

wherein

-   G is (CR^(3a)R^(3b))_(n);-   X is NR⁶ or CR⁷R⁸;-   R¹ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, phenyl, phenyl-C₁-C₂-alkyl and    a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated    or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4    heteroatoms or heteroatom groups independently selected from N, O,    S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups    as ring members, where the cyclic moieties in the three    last-mentioned radicals may be substituted with one or more    substituents R¹¹;-   each R² is independently selected from the group consisting of    cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄-alkyl C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    —NR^(12a)C(O)R¹⁰, —C(O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents-   R^(3a) and R^(3b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    -   —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),        C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy,        phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy        and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring containing 1, 2, 3 or        4 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the        cyclic moieties in the six last-mentioned radicals may be        substituted with one or more substituents R¹¹;-   R^(4a) and R^(4b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl,    -   —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰,        —C(═O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy,        fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl,        phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or        8-membered saturated, partially unsaturated or maximally        unsaturated ring containing 1, 2, 3 or 4 heteroatoms or        heteroatom groups independently selected from N, O, S, NO, SO,        SO₂, C═O and C═S as ring members, where the cyclic moieties in        the six last-mentioned radicals may be substituted with one or        more substituents R¹¹; or R^(4a) and R^(4b) form together a        group ═O or ═S;-   R^(5a) and R^(5b), independently of each other, are selected from    the group consisting of hydrogen, deuterium, halogen, cyano, nitro,    hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄ alkyl    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹¹; or    -   R^(5a) and R^(5b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹; or R^(5a) and R⁶, together with the atoms they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated heterocyclic ring, where        the ring may further contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹¹; or    -   R^(5a) and R⁷, together with the carbon atoms they are bound to,        form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹;-   R⁶ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, —SO₂R¹⁰, phenyl,    phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,    partially unsaturated or maximally unsaturated heterocyclic ring    containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO and SO₂ and optionally    also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic    moieties in the three last-mentioned radicals may be substituted    with one or more substituents R¹¹;-   R⁷ and R⁸, independently of each other, are selected from the group    consisting of deuterium, halogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    -   —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),        C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy,        phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy        and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring containing 1, 2, 3 or        4 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the        cyclic moieties in the six last-mentioned radicals may be        substituted with one or more substituents R¹¹; or    -   R⁷ and R⁸, together with the carbon atom they are bound to, form        a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring, where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹¹;-   each R⁹ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄ alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹¹; or    -   two radicals R⁹ bound on neighbouring carbon atoms, together        with the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-,        7- or 8-membered partially unsaturated or maximally unsaturated        ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹¹;-   each R¹⁰ is independently selected from the group consisting of    hydrogen, cyano, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), phenyl, phenyl    C₁-C₂ alkyl phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally unsaturated    ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the five last-mentioned    radicals may be substituted with one or more substituents R¹¹;-   each R¹¹ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —COOH, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,    C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl,    SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy and fluorinated    C₁-C₆-alkylcarbonyloxy;-   R^(12a) and R^(12b), independently of each other and independently    of each occurrence, are selected from the group consisting of    hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated    C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties    in the two last-mentioned radicals may carry 1, 2 or 3 substituents    selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,    -   if R^(12a) and R^(12b) are bound to the same nitrogen atom,        together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7-        or 8-membered saturated, partially unsaturated or maximally        unsaturated heterocyclic ring, where the ring may further        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated        C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;-   a is 0, 1 or 2;-   b is 0, 1, 2 or 3; and-   n is 1 or 2;    and the N-oxides, tautomeric forms, stereoisomers and    pharmaceutically acceptable salts thereof, and the compound of the    general formula I, wherein at least one of the atoms has been    replaced by its stable, non-radioactive isotope.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, or comprising at least onecompound as defined above or below wherein at least one of the atoms hasbeen replaced by its stable, non-radioactive isotope, preferably whereinat least one hydrogen atom has been replaced by a deuterium atom, incombination with at least one pharmaceutically acceptable carrier and/orauxiliary substance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which responds tothe modulation of the 5-HT_(2c) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2c) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders selected from the groupconsisting of damage of the central nervous system, disorders of thecentral nervous system, eating disorders, ocular hypertension,cardiovascular disorders, gastrointestinal disorders and diabetes, andespecially from the group consisting of bipolar disorder, depression,atypical depression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, behavioral disorders associated with dementia, social phobia,mental disorders in childhood, attention deficit hyperactivity disorder,organic mental disorders, autism, mutism, disruptive behavior disorder,impulse control disorder, borderline personality disorder, obsessivecompulsive disorder, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, seizuredisorders, epilepsy, substance use disorders, alcohol abuse, cocaineabuse, tobacco abuse, smoking cessation, sexual dysfunction/erectiledysfunction in males, sexual dysfunction in females, premenstrualsyndrome, late luteal phase syndrome, chronic fatigue syndrome, sleepdisorders, sleep apnoea, chronic fatigue syndrome, psoriasis,Parkinson's disease, spinal cord injury, trauma, stroke, pain, bladderdysfunction/urinary incontinence, encephalitis, meningitis, eatingdisorders, obesity, bulimia, weight loss, anorexia nervosa, ocularhypertension, cardiovascular disorders, gastrointestinal disorders,diabetes insipidus, diabetes mellitus, type I diabetes, type IIdiabetes, type III diabetes, diabetes secondary to pancreatic diseases,diabetes related to steroid use, diabetes complications, hyperglycemiaand insulin resistance.

In yet another aspect, the invention relates to a method for treatingdisorders which respond to the modulation of the 5-HT_(2c) receptor,which method comprises administering to a subject in need thereof atleast one compound of formula I or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention relates to a method for treatingdisorders selected from the group consisting of damage of the centralnervous system, disorders of the central nervous system, eatingdisorders, ocular hypertension, cardiovascular disorders,gastrointestinal disorders and diabetes, and especially from the groupconsisting of bipolar disorder, depression, atypical depression, moodepisodes, adjustment disorders, anxiety, panic disorders, post-traumaticsyndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia,memory loss, dementia of aging, Alzheimer's disease, behavioraldisorders associated with dementia, social phobia, mental disorders inchildhood, attention deficit hyperactivity disorder, organic mentaldisorders, autism, mutism, disruptive behavior disorder, impulse controldisorder, borderline personality disorder, obsessive compulsivedisorder, migraine and other conditions associated with cephalic pain orother pain, raised intracranial pressure, seizure disorders, epilepsy,substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse,smoking cessation, sexual dysfunction/erectile dysfunction in males,sexual dysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, spinal cordinjury, trauma, stroke, pain, bladder dysfunction/urinary incontinence,encephalitis, meningitis, eating disorders, obesity, bulimia, weightloss, anorexia nervosa, ocular hypertension, cardiovascular disorders,gastrointestinal disorders, diabetes insipidus, diabetes mellitus, typeI diabetes, type II diabetes, type III diabetes, diabetes secondary topancreatic diseases, diabetes related to steroid use, diabetescomplications, hyperglycemia and insulin resistance, which methodcomprises administering to a subject in need thereof at least onecompound of formula I or an N-oxide, a tautomeric form, a stereoisomeror a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The compounds of the formula I may exist in different spatialarrangements. For example, if the compounds possess one or more centersof asymmetry, polysubstituted rings or double bonds, or as differenttautomers, the present invention contemplates the possible use ofenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, such as the respective essentially pureenantiomers, diastereomers and tautomers of the compounds of formula Iand/or their salts.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formula I, especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid,C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromaticsulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Other utilizable acids are described inFortschritte der Arzneimittelforschung [Advances in drug research],Volume 10, pages 224 et seq., Birkhäauser Verlag, Basel and Stuttgart,1966.

The compounds of formula I may also be present in the form of tautomers.In one aspect, tautomery may be present in compounds I wherein R^(4a)and R^(ob) form together a group ═O and R^(5a) or R^(5b) is H. Forexample, the compounds of formula I may have the following tautomericformulae:

In another aspect, tautomery may be present in compounds I containingrings which have one or more C═O groups as ring members which areneighbored to a CH₂ group.

The organic moieties mentioned in the above definitions of the variablesare, like the term halogen, collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine. In one aspect, the halogen may be fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties of alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyland the like refers to saturated straight-chain or branched hydrocarbonradicals having 1 to 2 (“C₁-C₂-alkyl”), 1 to 3 (“C₁-C₃-alkyl”), 1 to 4(“C₁-C₄-alkyl”) or 1 to 6 (“C₁-C₆-alkyl”) carbon atoms. C₁-C₂-Alkyl ismethyl or ethyl. C₁-C₃-Alkyl is additionally propyl and isopropyl.C₁-C₄-Alkyl is additionally butyl, 1-methylpropyl (sec-butyl),2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C₁-C₆-Alkylis additionally also, for example, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or1-ethyl-2-methylpropyl.

The term “fluorinated alkyl” as used herein refers to straight-chain orbranched alkyl groups having 1 to 2 (“fluorinated C₁-C₂-alkyl”), 1 to 3(“fluorinated C₁-C₃-alkyl”), 1 to 4 (“fluorinated C₁-C₄-alkyl”) or 1 to6 (“fluorinated C₁-C₆-alkyl”) carbon atoms (as mentioned above), wheresome or all of the hydrogen atoms in these groups are replaced byfluorine atoms. Fluorinated C₁-C₂-alkyl is an alkyl group having 1 or 2carbon atoms (as mentioned above), where at least one of the hydrogenatoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replacedby fluorine atoms, such as difluoromethyl, trifluoromethyl,1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl.Fluorinated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms (as mentioned above), where at least one ofthe hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groupsare replaced by fluorine atoms. Examples are, apart those listed abovefor C₁-C₂-fluoroalkyl, 1-fluoropropyl, (R)-1-fluoropropyl,(S)-1-fluoropropyl, 2-fluoropropyl, (R)-2-fluoropropyl,(S)-2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl,2,2-difluoropropyl, 1,2-difluoropropyl, 2,3-difluoropropyl,1,3-difluoropropyl, 3,3-difluoropropyl, 1,1,2-trifluoropropyl,1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl, 2,2,3-trifluoropropyl,3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl, 2-fluoro-1-methylethyl,(R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl,2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl,(S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl,(R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl,2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl,(S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl,1-(difluoromethyl)-2,2-difluoroethyl,1-(trifluoromethyl)-2,2,2-trifluoroethyl,1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl,(R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, (R)-2-fluorobutyl,(S)-2-fluorobutyl, 3-fluorobutyl, (R)-3-fluorobutyl, (S)-3-fluorobutyl,4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like. FluorinatedC₁-C₆-alkyl is a straight-chain or branched alkyl group having 1 to 6carbon atoms (as mentioned above), where at least one of the hydrogenatoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replacedby fluorine atoms. Additionally examples include for C₁-C₄-fluoroalkyl,1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl,(R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl,(R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl,(R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl,(R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl,(R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl,(S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl,4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl,(R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl, (R)-6-fluorohexyl,(S)-6-fluorohexyl, and the like.

The term “alkenyl” as used herein refers to monounsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-alkenyl”), 2 to 4 (“C₂-C₄-alkenyl”) or 2 to 6 (“C₂-C₆-alkenyl”)carbon atoms and a double bond in any position, such as C₂-C₃-alkenyl,such as ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl;C₂-C₄-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl; andC₂-C₆-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl and the like.

The term “fluorinated alkenyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkenyl”), 2 to 4 (“fluorinated C₂-C₄-alkenyl”) or 2to 6 (“fluorinated C₂-C₆-alkenyl”) carbon atoms and a double bond in anyposition (as mentioned above), where some or all of the hydrogen atomsin these groups are replaced by fluorine atoms, such as, fluorovinyl,fluoroallyl and the like.

The term “alkynyl” as used herein refers to straight-chain or branchedhydrocarbon groups having 2 to 3 (“C₂-C₃-alkynyl”), 2 to 4(“C₂-C₄-alkynyl”) or 2 to 6 (“C₂-C₆-alkynyl”) carbon atoms and one ortwo triple bonds in any position, such as C₂-C₃-alkynyl, such asethynyl, 1-propynyl or 2-propynyl; C₂-C₄-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl and the like, and C₂-C₆-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl andthe like.

The term “fluorinated alkynyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkynyl”), 3 to 4 (“fluorinated C₃-C₄-alkynyl”) or 2to 6 (“fluorinated C₂-C₆-alkynyl”) carbon atoms and one or two triplebonds in any position (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by fluorine atoms.

The term “cycloalkyl” as used herein refers to mono- or bicyclicsaturated hydrocarbon radicals having 3 to 8 (“C₃-C₈-cycloalkyl”), inparticular 3 to 6 carbon atoms (“C₃-C₆-cycloalkyl”) or 3 to 5 carbonatoms (“C₃-C₅-cycloalkyl”) or 3 or 4 carbon atoms (“C₃-C₄-cycloalkyl”).In one aspect, C₃-C₄-cycloalkyl, C₃-C₅-cycloalkyl and C₃-C₆-cycloalkylare monocyclic. Examples for C₃-C₄-cycloalkyl are cyclopropyl andcyclobutyl. Examples of monocyclic radicals having 3 to 5 carbon atomsare cyclopropyl, cyclobutyl and cyclopentyl. Examples of monocyclicradicals having 3 to 6 carbon atoms are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Examples of monocyclic radicals having 3 to8 carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Examples of bicyclic radicals having 7 or 8carbon atoms comprise bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl. In one aspect, the termcycloalkyl denotes a monocyclic saturated hydrocarbon radical.

The term “fluorinated cycloalkyl” as used herein refers to mono- orbicyclic saturated hydrocarbon groups having 3 to 8(“C₃-C₈-halocycloalkyl”) or preferably 3 to 6 (“C₃-C₆-halocycloalkyl”)or 3 to 5 (“C₃-C₅-halocycloalkyl”) carbon ring members (as mentionedabove) in which some or all of the hydrogen atoms are replaced byfluorine atoms. Examples include 1-fluorocyclopropyl,2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl,1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl,pentafluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl,3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl,1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl, 2,3-difluorocyclobutyl,2,4-difluorocyclobutyl, 1,2,2-trifluorocyclobutyl, 1-fluorocycloheptyl,2-fluorocycloheptyl, 3-fluorocycloheptyl, 4-fluorocycloheptyl,1,2-difluorocycloheptyl, 1,3-difluorocycloheptyl,1,4-difluorocycloheptyl, 2,2-difluorocycloheptyl,2,3-difluorocycloheptyl, 2,4-difluorocycloheptyl,2,5-difluorocycloheptyl, 2,6-difluorocycloheptyl,2,7-difluorocycloheptyl, 3,3-difluorocycloheptyl,3,4-difluorocycloheptyl, 3,5-difluorocycloheptyl,3,6-difluorocycloheptyl, 4,4-difluorocycloheptyl,4,5-difluorocycloheptyl, and the like.

The term “cycloalkenyl” as used herein refers to monocyclic partiallyunsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“C₅-C₆-cycloalkenyl”) andone or more non-cumulative, preferably one, C—C double bonds in thering. Examples for C₅-C₆-cycloalkenyl are cyclopent-1-en-1-yl,cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl,cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl,cyclohex-1-en-3-yl, cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl,cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl,cyclohexa-1,4-dien-1-yl and cyclohexa-1,4-dien-3-yl. Examples ofC₅-C₇-cycloalkenyl are, apart those mentioned above, include forC₅-C₆-cycloalkenyl, cyclohept-1-en-1-yl, cyclohept-1-en-3-yl,cyclohept-1-en-4-yl, cyclohept-1-en-5-yl, cyclohepta-1,3-dien-1-yl,cyclohepta-1,3-dien-2-yl, cyclohepta-1,3-dien-5-yl,cyclohepta-1,3-dien-6-yl, cyclohepta-1,4-dien-1-yl,cyclohepta-1,4-dien-2-yl, cyclohepta-1,4-dien-3-yl andcyclohepta-1,4-dien-6-yl. Examples of C₃-C₈-cycloalkenyl are, apartthose mentioned above for C₅-C₆-cycloalkenyl, cycloprop-1-en-1-yl,cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl,cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl,cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl,cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl,cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl,cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, andcycloocta-1,5-dien-3-yl.

The term “fluorinated cycloalkenyl” as used herein refers to monocyclicpartially unsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“fluorinated C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“fluorinated C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“fluorinatedC₅-C₆-cycloalkenyl”) and one or more non-cumulative, preferably one, C—Cdouble bonds in the ring and in which some or all of the hydrogen atomsare replaced by fluorine atoms.

The term “C₁-C₂-alkoxy” is a C₁-C₂-alkyl group, as defined above,attached via an oxygen atom. The term “C₁-C₃-alkoxy” is a C₁-C₃-alkylgroup, as defined above, attached via an oxygen atom. The term“C₁-C₄-alkoxy” is a C₁-C₄-alkyl group, as defined above, attached via anoxygen atom. The term “C₁-C₆-alkoxy” is a C₁-C₆-alkyl group, as definedabove, attached via an oxygen atom. C₁-C₂-Alkoxy is methoxy or ethoxy.C₁-C₃-Alkoxy is additionally, for example, n-propoxy and 1-methylethoxy(isopropoxy). C₁-C₄-Alkoxy is additionally, for example, butoxy,1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or1,1-dimethylethoxy (tert-butoxy). C₁-C₆-Alkoxy is additionally, forexample, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy,1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy,3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy. C₁-C₈-Alkoxy is additionally, for example,heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof.

The term “fluorinated C₁-C₂-alkoxy” is a fluorinated C₁-C₂-alkyl group,as defined above, attached via an oxygen atom. The term “fluorinatedC₁-C₃-alkoxy” is a fluorinated C₁-C₃-alkyl group, as defined above,attached via an oxygen atom. The term “fluorinated C₁-C₆-haloalkoxy” isa fluorinated C₁-C₆-alkyl group, as defined above, attached via anoxygen atom. Fluorinated C₁-C₂-alkoxy is, for example, OCH₂F, OCHF₂,OCF₃, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy,2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy,2,2-difluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy,2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or OC₂F₅. FluorinatedC₁-C₃-alkoxy is additionally, for example, 1-fluoropropoxy,(R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy,(R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy,1,1-difluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,3,3-difluoropropoxy, 3,3,3-trifluoropropoxy,(R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy,(R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy,(R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy,(R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy,2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy,OCH₂—C₂F₅, OCF₂—C₂F₅ or 1-(CH₂F)-2-fluoroethoxy. FluorinatedC₁-C₄-alkoxy is additionally, for example, 1-fluorobutoxy,(R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy,4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy,3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy ornonafluorobutoxy. Fluorinated C₁-C₆-alkoxy is additionally, for example,5-fluoropentoxy, undecafluoropentoxy, 6-fluorohexoxy ortridecafluorohexoxy.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxygroup, as defined above. The term “C₁-C₆-alkoxy-C₁-C₄-alkyl” as usedherein, refers to a straight-chain or branched alkyl group having 1 to 4carbon atoms, as defined above, where one hydrogen atom is replaced by aC₁-C₆-alkoxy group, as defined above. Examples are methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl,sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl,1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl,2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl,1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl,1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl,1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl,2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl,2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl,3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.

The term “hydroxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxy group.The term “hydroxy-C₁-C₆-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 6 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxy group.Examples for hydroxy-C₁-C₄-alkyl include hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl,3-hydroxybut-2-yl, 4-hydroxybut-2-yl, hydroxy-tert-butyl and the like.Examples for hydroxy-C₁-C₆-alkyl are, apart those mentioned forhydroxy-C₁-C₄-alkyl, include, 1-hydroxypentyl, 2-hydroxypentyl,3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl,2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl,6-hydroxyhexyl and the like.

The term “hydroxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by ahydroxy group. The term “hydroxy-C₁-C₆-alkoxy” as used herein, refers toa C₁-C₆-alkoxy group, as defined above, where one hydrogen atom isreplaced by a hydroxy group. Examples for hydroxy-C₁-C₄-alkoxy includehydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy,2-hydroxypropoxy, 3-hydroxypropoxy, 1-hydroxy-2-propoxy,2-hydroxy-2-propoxy, 1-hydroxybutoxy, 2-hydroxybutoxy, 3-hydroxybutoxy,4-hydroxybutoxy, 1-hydroxy-2-butoxy, 2-hydroxy-2-butoxy,3-hydroxy-2-butoxy, 4-hydroxy-2-butoxy, hydroxy-tert-butoxy and thelike. Examples for hydroxy-C₁-C₆-alkoxy include, apart those mentionedfor hydroxy-C₁-C₄-alkoxy, 1-hydroxypentoxy, 2-hydroxypentoxy,3-hydroxypentoxy, 4-hydroxypentoxy, 5-hydroxypentoxy, 1-hydroxyhexoxy,2-hydroxyhexoxy, 3-hydroxyhexoxy, 4-hydroxyhexoxy, 5-hydroxyhexoxy,6-hydroxyhexoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkoxy” as used herein, refers to aC₁-C₄-alkoxy group, as defined above, where one hydrogen atom isreplaced by a C₁-C₄-alkoxy group, as defined above. The term“C₁-C₆-alkoxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by aC₁-C₄-alkoxy group, as defined above. Examples are methoxymethoxy,ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy,sec-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy,1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxyethoxy,1-butoxyethoxy, 1-sec-butoxyethoxy, 1-isobutoxyethoxy,1-tert-butoxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy,2-isopropoxyethoxy, 2-butoxyethoxy, 2-sec-butoxyethoxy,2-isobutoxyethoxy, 2-tert-butoxyethoxy, 1-methoxypropoxy,1-ethoxypropoxy, 1-propoxypropoxy, 1-isopropoxypropoxy, 1-butoxypropoxy,1-sec-butoxypropoxy, 1-isobutoxypropoxy, 1-tert-butoxypropoxy,2-methoxypropoxy, 2-ethoxypropoxy, 2-propoxypropoxy,2-isopropoxypropoxy, 2-butoxypropoxy, 2-sec-butoxypropoxy,2-isobutoxypropoxy, 2-tert-butoxypropoxy, 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, 3-isopropoxypropoxy, 3-butoxypropoxy,3-sec-butoxypropoxy, 3-isobutoxypropoxy, 3-tert-butoxypropoxy and thelike.

The term “C₁-C₂-alkylthio” is a C₁-C₂-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₃-alkylthio” refers to aC₁-C₃-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₄-alkylthio” is a C₁-C₄-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₆-alkylthio” refers to aC₁-C₆-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₁₀-alkylthio” refers to a C₁-C₁₀-alkyl group, as definedabove, attached via a sulfur atom. C₁-C₂-Alkylthio is methylthio orethylthio. C₁-C₃-Alkylthio is additionally, for example, n-propylthio or1-methylethylthio (isopropylthio). C₁-C₄-Alkylthio is additionally, forexample, butylthio, 1-methylpropylthio (sec-butylthio),2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio(tert-butylthio). C₁-C₆-Alkylthio is additionally, for example,pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio,1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio,3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio,2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.

The term “fluorinated C₁-C₂-alkylthio” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfur atom. Theterm “fluorinated C₁-C₃-alkylthio” refers to a fluorinated C₁-C₃-alkylgroup, as defined above, attached via a sulfur atom. The term“fluorinated C₁-C₄-alkylthio” refers to a fluorinated C₁-C₄-alkyl group,as defined above, attached via a sulfur atom. The term “fluorinatedC₁-C₆-alkylthio” refers to a fluorinated C₁-C₆-alkyl group, as definedabove, attached via a sulfur atom. Fluorinated C₁-C₂-alkylthio refersto, for example, SCH₂F, SCHF₂, SCF₃, 2-fluoroethylthio,2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, or SC₂F₅. FluorinatedC₁-C₃-alkylthio may additionally, for example, include2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio,2,3-difluoropropylthio, 3,3,3-trifluoropropylthio, SCH₂—C₂F₅, SCF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylthio. Fluorinated C₁-C₄-alkylthio mayadditionally, for example, include 4-fluorobutylthio ornonafluorobutylthio. Fluorinated C₁-C₆-alkylthio is additionally, forexample, 5-fluoropentylthio, undecafluoropentylthio, 6-fluorohexylthioor dodecafluorohexylthio.

The term “C₁-C₂-alkylsulfinyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfinyl [S(O)] group. The term“C₁-C₄-alkylsulfinyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group. The term “C₁-C₆-alkylsulfinyl” is aC₁-C₆-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl.C₁-C₄-Alkylsulfinyl is additionally, for example, n-propylsulfinyl,1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl,1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl(isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl).C₁-C₆-Alkylsulfinyl is additionally, for example, pentylsulfinyl,1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

The term “fluorinated C₁-C₂-alkylsulfinyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. The term “fluorinated C₁-C₃-alkylsulfinyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₄-alkylsulfinyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₆-alkylsulfinyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. Fluorinated C₁-C₂-alkylsulfinyl is, for example, S(O)CH₂F,S(O)CHF₂, S(O)CF₃, 2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, or S(O)C₂F₅. FluorinatedC₁-C₃-alkylsulfinyl may additionally, for example, include2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl,2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl,3,3,3-trifluoropropylsulfinyl, S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfinyl. Fluorinated C₁-C₄-alkylsulfinyl mayadditionally, for example, include 4-fluorobutylsulfinyl ornonafluorobutylsulfinyl. Fluorinated C₁-C₆-alkylsulfinyl mayadditionally, for example, include 5-fluoropentylsulfinyl,undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl ordodecafluorohexylsulfinyl.

The term “C₁-C₂-alkylsulfonyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfonyl [S(O)₂] group. The term“C₁-C₄-alkylsulfonyl” refers to a C₁-C₄-alkyl group, as defined above,attached via a sulfonyl [S(O)₂] group. The term “C₁-C₆-alkylsulfonyl” isa C₁-C₆-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. C₁-C₂-Alkylsulfonyl refers to a methylsulfonyl or ethylsulfonyl.C₁-C₄-Alkylsulfonyl is additionally, for example, n-propylsulfonyl,1-methylethylsulfonyl (isopropylsulfonyl), butylsulfonyl,1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl(isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl).C₁-C₆-Alkylsulfonyl is additionally, for example, pentylsulfonyl,1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.

The term “fluorinated C₁-C₂-alkylsulfonyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. The term “fluorinated C₁-C₃-alkylsulfonyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₄-alkylsulfonyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₆-alkylsulfonyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. Fluorinated C₁-C₂-alkylsulfonyl is, for example,S(O)₂CH₂F, S(O)₂CHF₂, S(O)₂CF₃, 2-fluoroethylsulfonyl,2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, or S(O)₂C₂F₅.Fluorinated C₁-C₃-alkylsulfonyl is additionally, for example,2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl,2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl,3,3,3-trifluoropropylsulfonyl, S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfonyl. Fluorinated C₁-C₄-alkylsulfonyl isadditionally, for example, 4-fluorobutylsulfonyl ornonafluorobutylsulfonyl. Fluorinated C₁-C₆-alkylsulfonyl isadditionally, for example, 5-fluoropentylsulfonyl,undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl ordodecafluorohexylsulfonyl.

C₁-C₄-Alkylcarbonyl refers to a straight-chain or branched alkyl grouphaving from 1 to 4 carbon atoms), which is bound to the remainder of themolecule via a carbonyl group (CO), such as in acetyl, propionyl,isopropylcarbonyl, butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl,and tert-butylcarbonyl. C₁-C₆-Alkylcarbonyl is a straight-chain orbranched alkyl group having from 1 to 6 carbon atoms, which is bound tothe remainder of the molecule via a carbonyl group (CO). Examplesinclude, apart those listed above for C₁-C₄-alkylcarbonylpentylcarbonyl,hexylcarbonyl and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyl refers to a straight-chain or branchedfluorinated alkyl group having from 1 to 4 carbon atoms as definedabove, which is bound to the remainder of the molecule via a carbonylgroup (CO). Fluorinated C₁-C₆-alkylcarbonyl is a straight-chain orbranched fluorinated alkyl group having from 1 to 6 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyl group (CO). Examples include trifluoromethylcarbonyl,2,2,2-trifluoroethylcarbonyl and the like.

C₁-C₆-Alkoxycarbonyl refers to a straight-chain or branched alkoxy grouphaving from 1 to 6, especially 1 to 4 carbon atoms(═C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbon atoms(═C₁-C₃-alkoxycarbonyl), which is bound to the remainder of the moleculevia a carbonyl group (CO), such as in methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, and isopropyloxycarbonyl.

Fluorinated C₁-C₆-alkoxycarbonyl refers to a straight-chain or branchedfluorinated alkoxy group having from 1 to 6, especially 1 to 4 carbonatoms (=fluorinated C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbonatoms (=fluorinated C₁-C₃-alkoxycarbonyl) as defined above, which isbound to the remainder of the molecule via a carbonyl group (CO).Examples include trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyland the like.

C₁-C₄-Alkylcarbonyloxy refers to a straight-chain or branched alkylgroup having from 1 to 4 carbon atoms, which is bound to the remainderof the molecule via a carbonyloxy group [C(O)—O—], such as inacet(yl)oxy, propionyloxy, isopropylcarbonyloxy, butylcarbonyloxy,sec-butylcarbonyloxy, isobutylcarbonyloxy, and tert-butylcarbonyloxy.C₁-C₆-Alkylcarbonyloxy is a straight-chain or branched alkyl grouphaving from 1 to 6 carbon atoms, which is bound to the remainder of themolecule via a carbonyloxy group [C(O—O—]. Examples include, apart thoselisted above for C₁-C₄-alkylcarbonyloxy, pentylcarbonyloxy,hexylcarbonyloxy and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyloxy refers to a straight-chain orbranched fluorinated alkyl group having from 1 to 4 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyloxy group [C(O)—O—]. Fluorinated C₁-C₆-alkylcarbonyloxy is astraight-chain or branched fluorinated alkyl group having from 1 to 6carbon atoms as defined above, which is bound to the remainder of themolecule via a carbonyloxy group [C(O)—O—]. Examples includetrifluoromethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy and thelike.

Phenyl-C₁-C₂-alkyl is a phenyl group bound to the remainder of themolecule via a C₁-C₂-alkyl group. Examples are benzyl, 1-phenylethyl and2-phenylethyl (phenethyl).

The term “3-, 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated heterocyclic ring containing 1, 2,3 or 4 heteroatoms or heteroatom groups independently selected from N,O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups asring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered, preferably a3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximumunsaturated heteromonocyclic ring containing 1, 2, 3 or 4 (preferably 1,2 or 3) heteroatoms or heteroatom groups selected from N, O, S, SO andSO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members.

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heterocyclic rings are aromatic.7- and 8-membered rings cannot be aromatic. They are homoaromatic(7-membered ring, 3 double bonds) or have 4 double bonds (8-memberedring). Partially unsaturated rings contain less than the maximum numberof C—C and/or C—N and/or N—N double bond(s) allowed by the ring size.The heterocyclic ring may be attached to the remainder of the moleculevia a carbon ring member or via a nitrogen ring member. As a matter ofcourse, the heterocyclic ring contains at least one carbon ring atom. Ifthe ring contains more than one 0 ring atom, these are not adjacent.

Examples of a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ringinclude: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl,azetidinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrofuran-2-on-3-yl, tetrahydrofuran-2-on-4-yl,tetrahydrofuran-2-on-5-yl, tetrahydrofuran-2-thion-3-yl,tetrahydrofuran-2-thion-4-yl, tetrahydrofuran-2-thion-5-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-2-on-3-yl,tetrahydrothien-2-on-4-yl, tetrahydrothien-2-on-5-yl,tetrahydrothien-2-thion-3-yl, tetrahydrothien-2-thion-4-yl,tetrahydrothien-2-thion-5-yl, pyrrolidin-1-yl, pyrrolidine-2-on-1-yl,pyrrolidine-2,5-dion-1-yl, pyrrolidine-2-thion-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrrolidine-2-on-3-yl, pyrrolidine-2-on-4-yl,pyrrolidine-2-on-5-yl, pyrrolidine-2,5-dion-3-yl,pyrrolidine-2-thion-3-yl, pyrrolidine-2-thion-4-yl,pyrrolidine-2-thion-5-yl, pyrazolidin-1-yl, pyrazolidin-3-yl,pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,imidazolidin-2-on-1-yl, imidazolidin-2-thion-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, imidazolidin-2-on-4-yl, imidazolidin-2-thion-4-yl,oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl,isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl,isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl,thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl,isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl,4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl,piperidin-2-on-1-yl, piperidin-2,5-dion-1-yl, piperidine-2-thion-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-2-on-3-yl,piperidin-2,5-dion-3-yl, piperidin-2-thion-3-yl, piperidin-4-yl,hexahydropyridazin-3-yl, hexahydropyridazin-4-yl,hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl and1,2,4-hexahydrotriazin-3-yl, morpholin-2-yl, morpholin-3-yl,morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl,1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl,1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan 1, 2, 3or -4-yl, oxepan 2, 3, 4 or -5-yl, hexahydro-1,3-diazepinyl,hexahydro-1,4-diazepinyl, hexahydro-1,3-oxazepinyl,hexahydro-1,4-oxazepinyl, hexahydro-1,3-dioxepinyl,hexahydro-1,4-dioxepinyl and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclicring further include oxocane, thiocane, azocane, [1,3]diazocane,[1,4]diazocane, [1,5]diazocane, [1,5]oxazocane and the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturatedheterocyclic ring include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl,2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl,2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl,2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3, -4-, -5, -6- or-7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedheterocyclic ring further include 1,2,3,4,5,6-hexahydroazocine,2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine,1,2,3,4,7,8-hexahydroazocine, 1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocine and the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered maximally unsaturated(including aromatic) heterocyclic ring include 5- or 6-memberedheteroaromatic rings, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl,1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl, and also homoaromaticradicals, such as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturatedheterocyclic ring further include[1,3]diazocine, [1,5]diazocine and[1,5]diazocine.

A 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═Oand C═S as ring members is either saturated, partially unsaturated andcarbocyclic (if it contains only C═O and/or C═S as heteroatom group andno further heteroatoms or heteroatom groups) or saturated, partiallyunsaturated or maximally unsaturated heterocyclic. Examples are, inaddition to the heterocyclic rings mentioned above, carbocyclic rings,such as cyclopropanonyl, cyclobutanonyl, cyclopentanonyl,cyclohexanonyl, cyclohexandionyl, cycloheptanonyl, cyclooctanonyl,cyclopropanthionyl, cyclobutanthionyl, cyclopentanthionyl,cyclohexanthionyl, cyclohexandithionyl, cycloheptanthionyl,cyclooctanthionyl, cyclopropenonyl, cyclopentenonyl, cyclohexenonyl andthe like.

The remarks made above and in the following with respect to preferredaspects of the invention, e.g. to preferred meanings of the variablesR¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R⁷, R⁸, R⁹,a, b and n of compounds I, to preferred compounds I and to preferredembodiments of the method or the use according to the invention, applyin each case on their own or in particular to combinations thereof.

In a preferred embodiment, R¹ is selected from hydrogen, cyano,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, —C(═O)R¹⁰, phenyl and benzyl,where the phenyl moiety in the two last-mentioned radicals may carry 1,2 or 3 radicals R¹¹, where R¹⁰ and R¹¹ have one of the general meaningsgiven above, or, in particular, one of the preferred meanings givenbelow.

In the above group —C(═O)R¹⁰ as a meaning for R¹, R¹⁰ is preferablyselected from C₁-C₄-alkyl and C₁-C₄-alkoxy and more preferably fromC₁-C₂-alkyl and tert-butoxy.

More preferably, R¹ is selected from hydrogen and C₁-C₆-alkyl, inparticular from hydrogen and methyl, and is specifically hydrogen.

In a preferred embodiment, R² is selected from cyano, nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinatedC₁-C₆-alkoxy, more preferably from C₁-C₆-alkyl, in particular frommethyl, ethyl, propyl and isopropyl, and is specifically methyl.

In a preferred embodiment, R^(3a) and R^(3b), independently of eachother, are selected from hydrogen, cyano, nitro, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy. Morepreferably, R^(1a) is selected from hydrogen, cyano, nitro, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy, andR^(3b) is hydrogen. Even more preferably, R^(3a) is selected fromhydrogen and methyl and R^(3b) is hydrogen. In particular, both R^(3a)and R^(3b) are hydrogen.

In a preferred embodiment, R^(4a) and R^(4b), independently of eachother, are selected from hydrogen, C₁-C₆-alkyl and fluorinatedC₁-C₆-alkyl or form together a group ═O. More preferably, they arehydrogen or form together a group ═O. In particular, both R^(4a) andR^(4b) are hydrogen.

In a preferred embodiment,

-   R^(5a) is selected from hydrogen, cyano, nitro, hydroxy,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated    C₁-C₆-alkoxy; and in case that X is CR⁷R⁸ is further selected from    halogen; or-   R^(5a) and R⁶, together with the atoms they are bound to, form a 3-,    4-, 5-, 6- or 7-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring, where the ring may further    contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups    selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and    where the ring may be substituted with one or more substituents R¹¹;    or-   R^(5a) and R⁷, together with the carbon atoms they are bound to,    form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated    or maximally unsaturated ring, where the ring may contain 1, 2, 3 or    4 heteroatoms or heteroatom-containing groups selected from O, S, N,    SO, SO₂, C═O and C═S as ring members, and where the ring may be    substituted with one or more substituents R¹¹; and-   R^(5b) is selected from hydrogen and deuterium and is preferably    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

More preferably,

-   R^(5a) is selected from hydrogen, C₁-C₆-alkyl and fluorinated    C₁-C₆-alkyl; and in case that X is CR⁷R⁸ is further selected from    halogen; and is preferably selected from hydrogen and methyl, or    -   R^(5a) and R⁶ form together a group (CH₂)_(r), where r is 2, 3,        4 or 5, preferably 2, 3 or 4; or    -   R^(5a) and R⁷ form together a group (CH₂)_(s), where s is 2, 3,        4 or 5, preferably 2, 3 or 4; and-   R^(5b) is selected from hydrogen and deuterium and is preferably    hydrogen.

In an alternatively preferred embodiment, R^(5a) and R^(5b), togetherwith the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedring, where the ring may contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹¹; and form in particular a 5- or 6-membered saturated orpartially unsaturated carbocyclic ring, and where the ring may besubstituted with one or more substituents R¹¹.

In one embodiment, X is NR⁶, where R⁶ has one of the general meaningsgiven above, or, in particular, one of the preferred meanings givenbelow.

Preferably,

-   R⁶ is selected from the group consisting of hydrogen, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, —C(═O)R¹⁰, —SO₂R¹⁰, phenyl and benzyl,    where the phenyl moiety in the two last-mentioned radicals may carry    1, 2 or 3 radicals R¹¹; or-   R^(5a) and R⁶, together with the atoms they are bound to, form a 3-,    4-, 5-, 6- or 7-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring, where the ring may further    contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups    selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and    where the ring may be substituted with one or more substituents R¹¹;    where R¹⁰ and R¹¹ have one of the general meanings given above, or,    in particular, one of the preferred meanings given below.

In the above group —C(═O)R¹⁰, R⁶, R¹⁰ is preferably selected fromC₁-C₄-alkyl and C₁-C₄-alkoxy and more preferably from C₁-C₂-alkyl andtert-butoxy.

In the above group —SO₂R¹⁰, R⁶, R¹⁰ is preferably selected fromC₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and phenyl, where phenyl may besubstituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3, in particular 1,radicals R¹¹, where R¹¹ has one of the general meanings given above, or,in particular, one of the preferred meanings given below.

In one more preferred embodiment, R⁶ is —SO₂R¹⁰, where R¹⁰ has one ofthe general meanings given above or is preferably selected fromC₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and phenyl, where phenyl may besubstituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3, in particular 1,radicals R¹¹, where R¹¹ has one of the general meanings given above, or,in particular, one of the preferred meanings given below.

In another preferred embodiment, R⁶ is selected from C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₂-alkyl, fluorinated C₃-C₆-cycloalkyl-C₁-C₂-alkyl,phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5- or 6-membered saturatedheterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO and SO₂ andoptionally also 1 or 2 C═O and/or C═S groups as ring members, where thecyclic moieties in the three last-mentioned radicals may be substitutedwith one or more substituents R¹¹.

In a more preferred embodiment, R⁶ is phenyl-C₁-C₂-alkyl, and inparticular benzyl.

In another more preferred embodiment, R⁶ is selected from C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₂-alkyl and fluorinatedC₃-C₆-cycloalkyl-C₁-C₂-alkyl, and in particular from C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-methyl and fluorinated C₃-C₆-cycloalkyl-methyl.

In another more preferred embodiment, R⁶ is a 3-, 4-, 5- or 6-memberedsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO and SO₂and optionally also 1 or 2 C═O and/or C═S groups as ring members, wherethe cyclic moieties in the three last-mentioned radicals may besubstituted with one or more substituents R¹¹. Even more preferably, R⁶is a 3-, 4- or 5-membered saturated heterocyclic ring containing 1 or 2heteroatoms independently selected from N, O and S, where theheterocyclic ring may be substituted with one or two substituentsselected from halogen and C₁-C₄-alkyl, and is in particular oxetanylwhich may carry one or two substituents selected from halogen andC₁-C₄-alkyl and especially from F.

In another more preferred embodiment, R^(5a) and R⁶, together with theatoms they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated,partially unsaturated or maximally unsaturated heterocyclic ring, wherethe ring may further contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹¹;

where R¹¹ has one of the general meanings given above, or, inparticular, one of the preferred meanings given below.

In particular, R^(5a) and R⁶ form together a group (CH₂)_(r), where r is2, 3, 4 or 5, preferably 2, 3 or 4.

In an alternative embodiment, X is CR⁷R⁸, where R⁷ and R⁸ have one ofthe general meanings given above, or, in particular, one of thepreferred meanings given below.

In case that R⁷ and R⁸, together with the carbon atom they are bound to,form a ring, this ring is spiro-bound to the carbon atom carrying R⁷ andR⁸.

Preferably,

-   R⁷ and R⁸, independently of each other, are selected from the group    consisting of halogen, cyano, nitro, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b),    -   NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b),        C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy,        phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy        and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring containing 1, 2, 3 or        4 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the        cyclic moieties in the six last-mentioned radicals may be        substituted with one or more substituents R¹¹; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4    heteroatoms or heteroatom-containing groups selected from O, S, N,    SO, SO₂, C═O and C═S as ring members, and where the ring may be    substituted with one or more substituents R¹¹; or-   R^(5a) and R⁷, together with the carbon atoms they are bound to,    form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially    unsaturated or maximally unsaturated ring, where the ring may    contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups    selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and    where the ring may be substituted with one or more substituents R¹¹;-   in which case R⁸ has one of the above meanings or is deuterium;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

More preferably,

-   R⁷ and R⁸, independently of each other, are selected from halogen,    cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, phenyl, phenyl-C₁-C₂-alkyl, benzyloxy and    a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the four    last-mentioned radicals may be substituted with one or more    substituents R¹¹; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6- or 7- or 8-membered saturated, partially unsaturated    or maximally unsaturated ring, where the ring may contain 1, 2, 3 or    4 heteroatoms or heteroatom-containing groups selected from O, S, N,    SO, SO₂, C═O and C═S as ring members, and where the ring may be    substituted with one or more substituents R¹¹; or-   R^(5a) and R⁷, together with the carbon atoms they are bound to,    form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated    or maximally unsaturated ring, where the ring may contain 1, 2, 3 or    4 heteroatoms or heteroatom-containing groups selected from O, S, N,    SO, SO₂, C═O and C═S as ring members, and where the ring may be    substituted with one or more substituents R¹¹;-   in which case R⁸ has one of the above meanings or is deuterium; and-   R^(5b) is selected from hydrogen and deuterium and is preferably    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

Even more preferably,

-   R⁷ and R⁸, independently of each other, are selected from halogen,    cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and phenyl, or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6- or 7- or 8-membered saturated, partially unsaturated    or maximally unsaturated ring, where the ring may be substituted    with one or more substituents R¹¹; or-   R⁵ and R⁷ form together a group (CH₂)_(s), where s is 2, 3, 4 or 5,    preferably 2, 3 or 4;-   in which case R⁸ has one of the above meanings or is deuterium; and-   R^(5b) is selected from hydrogen and deuterium and is preferably    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

In particular,

-   R⁸ is selected from halogen, cyano, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl and phenyl; and-   R⁷ is selected from C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl,    preferably from methyl and CF₃ and is in particular methyl; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6- or 7- or 8-membered saturated, partially unsaturated    or maximally unsaturated ring, where the ring may be substituted    with one or more substituents R¹¹; or-   R^(5a) and R⁷ form together a group (CH₂)_(s), where s is 2, 3, 4 or    5, preferably 2, 3 or 4;-   in which case R⁸ has one of the above meanings or is deuterium; and-   R^(5b) is selected from hydrogen and deuterium and is preferably    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

Specifically,

-   R⁸ is selected from C₁-C₄-alkyl, fluorinated C₁-C₂-alkyl and phenyl    and specifically from methyl, CF₃ and phenyl; and-   R⁷ is methyl; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5- or 6-membered saturated or partially unsaturated ring,    where the ring may be substituted with one or more substituents R¹¹;    or-   R^(5a) and R⁷ form together a group (CH₂)_(s), where s is 3 or 4,    specifically 3;-   in which case R⁸ is selected from methyl and deuterium; and-   R^(5b) is selected from hydrogen and deuterium and is specifically    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

Very specifically,

-   R⁸ is selected from methyl, CF₃ and phenyl; and-   R⁷ is methyl; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    4, 5- or 6-membered saturated or partially unsaturated ring, where    the ring may be substituted with one or more substituents R¹¹; or-   R^(5a) and R⁷ form together a group (CH₂)_(s), where s is 3 or 4,    specifically 3;-   in which case R⁸ is selected from methyl and deuterium; and-   R^(5b) is selected from hydrogen and deuterium and is specifically    hydrogen;    where R¹¹ has one of the general meanings given above, or, in    particular, one of the preferred meanings given below.

In one particular embodiment, the ring formed by R⁷ and R⁸ together withthe carbon atom they are bound to is a carbocyclic ring, preferably asaturated or partially unsaturated carbocyclic ring.

If R⁷ and R⁸, together with the carbon atom they are bound to, form acarbocyclic ring, this is particularly preferably a 4- or 5-memberedsaturated carbocyclic ring (i.e. R⁷ and R⁸ form together a group—(CH₂)₃— or —(CH₂)₄—) and in particular a 4-membered saturatedcarbocyclic ring (i.e. R⁷ and R⁸ form together a group —(CH₂)₃—), wherethe ring may be substituted with one or more substituents R¹¹.Specifically, the ring is not substituted.

In an alternative particular embodiment, the ring formed by R⁷ and R⁸together with the carbon atom they are bound to is a heterocyclic ringcontaining 1, 2, 3 or 4 heteroatoms or heteroatom-containing groupsselected from O, S, N, SO and SO₂ as ring members, preferably containing1 or 2 heteroatoms or heteroatom-containing groups selected from O, S,N, SO and SO₂ as ring members. Preferably, the heterocyclic ring is 3-,4-, 5- or 6-membered and saturated and may carry one or moresubstituents R¹¹. In particular, the heterocyclic ring is oxetanyl whichmay carry one or more substituents R¹¹.

In a preferred embodiment, each R⁹ is independently selected fromhalogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy and a 3-, 4-, 5- or 6-membered saturatedheterocyclic ring containing 1 or 2 heteroatoms or heteroatom groupsindependently selected from N, O, S, NO, SO and SO₂ as ring members,where the heterocyclic ring may be substituted with one or moresubstituents R¹¹. The heterocyclic ring is specifically oxetanyl.

More preferably, each R⁹ is independently selected from halogen, cyano,nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy andfluorinated C₁-C₆-alkoxy, even more preferably from halogen, cyano,C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinatedC₁-C₄-alkoxy, and is in particular halogen, especially F or Cl, and morespecifically F.

In a preferred embodiment, R¹⁰ is selected from hydrogen, hydroxy,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), phenyl,phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedring containing 1, 2, 3 or 4 heteroatoms or heteroatom groupsindependently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ringmembers, where the cyclic moieties in the five last-mentioned radicalsmay be substituted with one or more substituents R¹¹, where R¹¹, R^(12a)and R^(12b) have one of the general meanings given above, or, inparticular, one of the preferred meanings given below. More preferably,R¹⁰ is selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy, and even more preferably fromC₁-C₄-alkyl and C₁-C₄-alkoxy. In particular, R¹⁰ is selected fromC₁-C₂-alkyl and tert-butoxy.

In a preferred embodiment, each R¹¹ is independently selected fromhalogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy, and is in particular halogenor C₁-C₄-alkyl.

In a preferred embodiment, R^(12a) and R^(12b), independently of eachother and independently of each occurrence, are selected from hydrogen,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, fluorinatedC₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinatedC₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties inthe two last-mentioned radicals may carry 1, 2 or 3 substituentsselected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,

if R^(12a) and R^(12b) are bound to the same nitrogen atom, togetherwith this nitrogen atom may form a 3-, 4-, 5-, 6- or 7-memberedsaturated, partially unsaturated or maximally unsaturated heterocyclicring, where the ring may further contain 1 or 2 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents selected from halogen, cyano nitro, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy.

More preferably, R^(12a) and R^(12b), independently of each other andindependently of each occurrence, are selected from hydrogen,C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl and benzyl, wherethe phenyl moiety in the last-mentioned radical may carry 1, 2 or 3substituents selected from halogen, cyano nitro, C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy; or,if R^(12a) and R^(12b) are bound to the same nitrogen atom, togetherwith this nitrogen atom may form a 5- or 6-membered saturated oraromatic heterocyclic ring, where the ring may further contain 1 or 2heteroatoms or heteroatom-containing groups selected from O, S, N, SO,SO₂ and C═O as ring members, and where the ring may be substituted with1 or 2 substituents selected from halogen, cyano nitro, C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy.

In particular, R^(12a) and R^(12b), independently of each other andindependently of each occurrence, are selected from hydrogen andC₁-C₆-alkyl.

In a preferred embodiment, a is 0 or 1 and in particular 0.

In a preferred embodiment, b is 0, 1 or 2 and in particular 0 or 1.

In a preferred embodiment, n is 1.

In a particular embodiment, the compound of formula I is a compound offormula I.1

wherein X, R^(5a), R^(5b), R⁹ and b have one of the above general, or,in particular, one of the above preferred meanings.

In a specific embodiment, the compound of formula I is a compound offormula I.1.1

wherein

-   R^(9a) is H or F; and-   R^(5a), R^(5b), R⁶, R⁹ and b have one of the above general, or, in    particular, one of the above preferred meanings.

In another specific embodiment, the compound of formula I is a compoundof formula I.1.2

wherein

-   R⁷ is selected from C₁-C₄-alkyl and fluorinated C₁-C₄-alkyl,    preferably from methyl and CF₃, and is in particular methyl;-   R⁸ is selected from C₁-C₄-alkyl and fluorinated C₁-C₄-alkyl, and    preferably from methyl and CF₃; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated    ring, where the ring may be substituted with one or more    substituents R¹¹, and form preferably a 5- or 6-membered saturated    or partially unsaturated ring;-   R^(9a) is H or F; and-   R⁹ and b have one of the above general, or, in particular, one of    the above preferred meanings.

In another specific embodiment, the compound of formula I is a compoundof formula I.1.3

wherein R⁸ is selected from deuterium, F, Cl and CN.

In another particular embodiment, the compound of formula I is acompound of formula I.2

wherein X, R^(5a), R^(5b), R⁹ and b have one of the above general, or,in particular, one of the above preferred meanings.

In another particular embodiment, the compound of formula I is acompound of formula I.2.1

wherein

-   R^(9a) is H or F; and-   R^(5a), R^(5b), R⁶, R⁹ and b have one of the above general, or, in    particular, one of the above preferred meanings.

In another particular embodiment, the compound of formula I is acompound of formula I.2.2

wherein

-   R^(2a), R^(2b), R^(3a) and R^(5a), independently of each other, are    selected from hydrogen and methyl;-   R⁷ is selected from C₁-C₄-alkyl and fluorinated C₁-C₄-alkyl,    preferably from methyl and CF₃, and is in particular methyl;-   R⁸ is selected from C₁-C₄-alkyl and fluorinated C₁-C₄-alkyl, and    preferably from methyl and CF₃; or-   R⁷ and R⁸, together with the carbon atom they are bound to, form a    3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated    ring, where the ring may be substituted with one or more    substituents R¹¹;-   R^(9a) is H or F; and-   R⁹ and b have one of the above general, or, in particular, one of    the above preferred meanings.

In the above formulae I.1.1, I.1.2, I.2.1 and I.2.2, (b-1) is preferably0.

Preferably, in the above formulae I.2, I.2.1 and I.2.2, R^(2a), R^(2b),R^(3a) and R^(5a) are selected from hydrogen and methyl, with theproviso that at most two, preferably at most one, of the substituentsR^(2a), R^(2b), R^(3a) and R^(5a) are methyl. In particular, R^(2b) ishydrogen and R^(2a), R^(3a) and R^(5a) are selected from hydrogen andmethyl, with the proviso that at most two, preferably at most one, ofthe substituents R^(2a), R^(3a) and R^(5a) are methyl.

Preferably, in the above formulae I.2, I.2.1 and I.2.2, R⁷ and R⁸,together with the carbon atom they are bound to, form a 4-, 5- or6-membered saturated or partially unsaturated carbocyclic ring,preferably a 4- or 5-membered saturated carbocyclic ring, in particulara 4-membered saturated carbocyclic ring, where the ring may besubstituted with one or more substituents R¹¹.

Examples of preferred compounds are compounds of the following formulaeLa to I.u, where the variables have one of the general or preferredmeanings given above. Examples of preferred compounds are the individualcompounds compiled in the tables 1 to 21 below. Moreover, the meaningsmentioned below for the individual variables in the tables are per se,independently of the combination in which they are mentioned, aparticularly preferred embodiment of the substituents in question.

Table 1

Compounds of the formula La in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 2

Compounds of the formula I.b in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 3

Compounds of the formula I.c in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 4

Compounds of the formula I.d in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 5

Compounds of the formula I.e in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 6

Compounds of the formula I.f in which the combination of R^(5a), R^(5b),R⁶ and R^(9a) for a compound corresponds in each case to one row ofTable A.

Table 7

Compounds of the formula I.g in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 8

Compounds of the formula I.h in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 9

Compounds of the formula I.i in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 10

Compounds of the formula I.j in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 11

Compounds of the formula I.k in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 12

Compounds of the formula I.l in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 13

Compounds of the formula I.m in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 14

Compounds of the formula I.n in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 15

Compounds of the formula I.o in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 16

Compounds of the formula I.p in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 17

Compounds of the formula I.q in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 18

Compounds of the formula I.r in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 19

Compounds of the formula I.s in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 20

Compounds of the formula I.t in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

Table 21

Compounds of the formula I.u in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) for a compound corresponds in each case to one row ofTable B.

TABLE A No. R^(9a) R^(5b) R^(5a) R⁶ A-1 H H H —SO₂—CH₃ A-2 F H H—SO₂—CH₃ A-3 Cl H H —SO₂—CH₃ A-4 Br H H —SO₂—CH₃ A-5 CH₃ H H —SO₂—CH₃A-6 CF₃ H H —SO₂—CH₃ A-7 OCH₃ H H —SO₂—CH₃ A-8 OCF₃ H H —SO₂—CH₃ A-9 HCH₃ H —SO₂—CH₃ A-10 F CH₃ H —SO₂—CH₃ A-11 Cl CH₃ H —SO₂—CH₃ A-12 Br CH₃H —SO₂—CH₃ A-13 CH₃ CH₃ H —SO₂—CH₃ A-14 CF₃ CH₃ H —SO₂—CH₃ A-15 OCH₃ CH₃H —SO₂—CH₃ A-16 OCF₃ CH₃ H —SO₂—CH₃ A-17 H CH₃ CH₃ —SO₂—CH₃ A-18 F CH₃CH₃ —SO₂—CH₃ A-19 Cl CH₃ CH₃ —SO₂—CH₃ A-20 Br CH₃ CH₃ —SO₂—CH₃ A-21 CH₃CH₃ CH₃ —SO₂—CH₃ A-22 CF₃ CH₃ CH₃ —SO₂—CH₃ A-23 OCH₃ CH₃ CH₃ —SO₂—CH₃A-24 OCF₃ CH₃ CH₃ —SO₂—CH₃ A-25 H H H —SO₂—CH₂CH₃ A-26 F H H —SO₂—CH₂CH₃A-27 Cl H H —SO₂—CH₂CH₃ A-28 Br H H —SO₂—CH₂CH₃ A-29 CH₃ H H —SO₂—CH₂CH₃A-30 CF₃ H H —SO₂—CH₂CH₃ A-31 OCH₃ H H —SO₂—CH₂CH₃ A-32 OCF₃ H H—SO₂—CH₂CH₃ A-33 H CH₃ H —SO₂—CH₂CH₃ A-34 F CH₃ H —SO₂—CH₂CH₃ A-35 ClCH₃ H —SO₂—CH₂CH₃ A-36 Br CH₃ H —SO₂—CH₂CH₃ A-37 CH₃ CH₃ H —SO₂—CH₂CH₃A-38 CF₃ CH₃ H —SO₂—CH₂CH₃ A-39 OCH₃ CH₃ H —SO₂—CH₂CH₃ A-40 OCF₃ CH₃ H—SO₂—CH₂CH₃ A-41 H CH₃ CH₃ —SO₂—CH₂CH₃ A-42 F CH₃ CH₃ —SO₂—CH₂CH₃ A-43Cl CH₃ CH₃ —SO₂—CH₂CH₃ A-44 Br CH₃ CH₃ —SO₂—CH₂CH₃ A-45 CH₃ CH₃ CH₃—SO₂—CH₂CH₃ A-46 CF₃ CH₃ CH₃ —SO₂—CH₂CH₃ A-47 OCH₃ CH₃ CH₃ —SO₂—CH₂CH₃A-48 OCF₃ CH₃ CH₃ —SO₂—CH₂CH₃ A-49 H H H —SO₂—CF₃ A-50 F H H —SO₂—CF₃A-51 Cl H H —SO₂—CF₃ A-52 Br H H —SO₂—CF₃ A-53 CH₃ H H —SO₂—CF₃ A-54 CF₃H H —SO₂—CF₃ A-55 OCH₃ H H —SO₂—CF₃ A-56 OCF₃ H H —SO₂—CF₃ A-57 H CH₃ H—SO₂—CF₃ A-58 F CH₃ H —SO₂—CF₃ A-59 Cl CH₃ H —SO₂—CF₃ A-60 Br CH₃ H—SO₂—CF₃ A-61 CH₃ CH₃ H —SO₂—CF₃ A-62 CF₃ CH₃ H —SO₂—CF₃ A-63 OCH₃ CH₃ H—SO₂—CF₃ A-64 OCF₃ CH₃ H —SO₂—CF₃ A-65 H CH₃ CH₃ —SO₂—CF₃ A-66 F CH₃ CH₃—SO₂—CF₃ A-67 Cl CH₃ CH₃ —SO₂—CF₃ A-68 Br CH₃ CH₃ —SO₂—CF₃ A-69 CH₃ CH₃CH₃ —SO₂—CF₃ A-70 CF₃ CH₃ CH₃ —SO₂—CF₃ A-71 OCH₃ CH₃ CH₃ —SO₂—CF₃ A-72OCF₃ CH₃ CH₃ —SO₂—CF₃ A-73 H H H —SO₂—C₆H₅* A-74 F H H —SO₂—C₆H₅ A-75 ClH H —SO₂—C₆H₅ A-76 Br H H —SO₂—C₆H₅ A-77 CH₃ H H —SO₂—C₆H₅ A-78 CF₃ H H—SO₂—C₆H₅ A-79 OCH₃ H H —SO₂—C₆H₅ A-80 OCF₃ H H —SO₂—C₆H₅ A-81 H CH₃ H—SO₂—C₆H₅ A-82 F CH₃ H —SO₂—C₆H₅ A-83 Cl CH₃ H —SO₂—C₆H₅ A-84 Br CH₃ H—SO₂—C₆H₅ A-85 CH₃ CH₃ H —SO₂—C₆H₅ A-86 CF₃ CH₃ H —SO₂—C₆H₅ A-87 OCH₃CH₃ H —SO₂—C₆H₅ A-88 OCF₃ CH₃ H —SO₂—C₆H₅ A-89 H CH₃ CH₃ —SO₂—C₆H₅ A-90F CH₃ CH₃ —SO₂—C₆H₅ A-91 Cl CH₃ CH₃ —SO₂—C₆H₅ A-92 Br CH₃ CH₃ —SO₂—C₆H₅A-93 CH₃ CH₃ CH₃ —SO₂—C₆H₅ A-94 CF₃ CH₃ CH₃ —SO₂—C₆H₅ A-95 OCH₃ CH₃ CH₃—SO₂—C₆H₅ A-96 OCF₃ CH₃ CH₃ —SO₂—C₆H₅ A-97 H H H —SO₂—C₆H₄CH₃** A-98 F HH —SO₂—C₆H₄CH₃ A-99 Cl H H —SO₂—C₆H₄CH₃ A-100 Br H H —SO₂—C₆H₄CH₃ A-101CH₃ H H —SO₂—C₆H₄CH₃ A-102 CF₃ H H —SO₂—C₆H₄CH₃ A-103 OCH₃ H H—SO₂—C₆H₄CH₃ A-104 OCF₃ H H —SO₂—C₆H₄CH₃ A-105 H CH₃ H —SO₂—C₆H₄CH₃A-106 F CH₃ H —SO₂—C₆H₄CH₃ A-107 Cl CH₃ H —SO₂—C₆H₄CH₃ A-108 Br CH₃ H—SO₂—C₆H₄CH₃ A-109 CH₃ CH₃ H —SO₂—C₆H₄CH₃ A-110 CF₃ CH₃ H —SO₂—C₆H₄CH₃A-111 OCH₃ CH₃ H —SO₂—C₆H₄CH₃ A-112 OCF₃ CH₃ H —SO₂—C₆H₄CH₃ A-113 H CH₃CH₃ —SO₂—C₆H₄CH₃ A-114 F CH₃ CH₃ —SO₂—C₆H₄CH₃ A-115 Cl CH₃ CH₃—SO₂—C₆H₄CH₃ A-116 Br CH₃ CH₃ —SO₂—C₆H₄CH₃ A-117 CH₃ CH₃ CH₃—SO₂—C₆H₄CH₃ A-118 CF₃ CH₃ CH₃ —SO₂—C₆H₄CH₃ A-119 OCH₃ CH₃ CH₃—SO₂—C₆H₄CH₃ A-120 OCF₃ CH₃ CH₃ —SO₂—C₆H₄CH₃ A-121 H H H benzyl A-122 FH H benzyl A-123 Cl H H benzyl A-124 Br H H benzyl A-125 CH₃ H H benzylA-126 CF₃ H H benzyl A-127 OCH₃ H H benzyl A-128 OCF₃ H H benzyl A-129 HCH₃ H benzyl A-130 F CH₃ H benzyl A-131 Cl CH₃ H benzyl A-132 Br CH₃ Hbenzyl A-133 CH₃ CH₃ H benzyl A-134 CF₃ CH₃ H benzyl A-135 OCH₃ CH₃ Hbenzyl A-136 OCF₃ CH₃ H benzyl A-137 H CH₃ CH₃ benzyl A-138 F CH₃ CH₃benzyl A-139 Cl CH₃ CH₃ benzyl A-140 Br CH₃ CH₃ benzyl A-141 CH₃ CH₃ CH₃benzyl A-142 CF₃ CH₃ CH₃ benzyl A-143 OCH₃ CH₃ CH₃ benzyl A-144 OCF₃ CH₃CH₃ benzyl A-145 H H —(CH₂)₃— A-146 F H —(CH₂)₃— A-147 Cl H —(CH₂)₃—A-148 Br H —(CH₂)₃— A-149 CH₃ H —(CH₂)₃— A-150 CF₃ H —(CH₂)₃— A-151 OCH₃H —(CH₂)₃— A-152 OCF₃ H —(CH₂)₃— A-153 H CH₃ —(CH₂)₃— A-154 F CH₃—(CH₂)₃— A-155 Cl CH₃ —(CH₂)₃— A-156 Br CH₃ —(CH₂)₃— A-157 CH₃ CH₃—(CH₂)₃— A-158 CF₃ CH₃ —(CH₂)₃— A-159 OCH₃ CH₃ —(CH₂)₃— A-160 OCF₃ CH₃—(CH₂)₃— A-161 H D —(CH₂)₃— A-162 F D —(CH₂)₃— A-163 Cl D —(CH₂)₃— A-164Br D —(CH₂)₃— A-165 CH₃ D —(CH₂)₃— A-166 CF₃ D —(CH₂)₃— A-167 OCH₃ D—(CH₂)₃— A-168 OCF₃ D —(CH₂)₃— A-169 H H —(CH₂)₄— A-170 F H —(CH₂)₄—A-171 Cl H —(CH₂)₄— A-172 Br H —(CH₂)₄— A-173 CH₃ H —(CH₂)₄— A-174 CF₃ H—(CH₂)₄— A-175 OCH₃ H —(CH₂)₄— A-176 OCF₃ H —(CH₂)₄— A-177 H CH₃—(CH₂)₄— A-178 F CH₃ —(CH₂)₄— A-179 Cl CH₃ —(CH₂)₄— A-180 Br CH₃—(CH₂)₄— A-181 CH₃ CH₃ —(CH₂)₄— A-182 CF₃ CH₃ —(CH₂)₄— A-183 OCH₃ CH₃—(CH₂)₄— A-184 OCF₃ CH₃ —(CH₂)₄— A-185 H D —(CH₂)₄— A-186 F D —(CH₂)₄—A-187 Cl D —(CH₂)₄— A-188 Br D —(CH₂)₄— A-189 CH₃ D —(CH₂)₄— A-190 CF₃ D—(CH₂)₄— A-191 OCH₃ D —(CH₂)₄— A-192 OCF₃ D —(CH₂)₄— A-193 H H —(CH₂)₅—A-194 F H —(CH₂)₅— A-195 Cl H —(CH₂)₅— A-196 Br H —(CH₂)₅— A-197 CH₃ H—(CH₂)₅— A-198 CF₃ H —(CH₂)₅— A-199 OCH₃ H —(CH₂)₅— A-200 OCF₃ H—(CH₂)₅— A-201 H CH₃ —(CH₂)₅— A-202 F CH₃ —(CH₂)₅— A-203 Cl CH₃ —(CH₂)₅—A-204 Br CH₃ —(CH₂)₅— A-205 CH₃ CH₃ —(CH₂)₅— A-206 CF₃ CH₃ —(CH₂)₅—A-207 OCH₃ CH₃ —(CH₂)₅— A-208 OCF₃ CH₃ —(CH₂)₅— A-209 H D —(CH₂)₅— A-210F D —(CH₂)₅— A-211 Cl D —(CH₂)₅— A-212 Br D —(CH₂)₅— A-213 CH₃ D—(CH₂)₅— A-214 CF₃ D —(CH₂)₅— A-215 OCH₃ D —(CH₂)₅— A-216 OCF₃ D—(CH₂)₅— *C₆H₅ = phenyl **C₆H₄CH₃ = 4-methylphenyl (p-tolyl)

TABLE B No. R^(9a) R^(5b) R^(5a) R⁷ R⁸ B-1 H H H CH₃ CH₃ B-2 F H H CH₃CH₃ B-3 Cl H H CH₃ CH₃ B-4 Br H H CH₃ CH₃ B-5 CH₃ H H CH₃ CH₃ B-6 CF₃ HH CH₃ CH₃ B-7 OCH₃ H H CH₃ CH₃ B-8 OCF₃ H H CH₃ CH₃ B-9 H F H CH₃ CH₃B-10 F F H CH₃ CH₃ B-11 Cl F H CH₃ CH₃ B-12 Br F H CH₃ CH₃ B-13 CH₃ F HCH₃ CH₃ B-14 CF₃ F H CH₃ CH₃ B-15 OCH₃ F H CH₃ CH₃ B-16 OCF₃ F H CH₃ CH₃B-17 H Cl H CH₃ CH₃ B-18 F Cl H CH₃ CH₃ B-19 Cl Cl H CH₃ CH₃ B-20 Br ClH CH₃ CH₃ B-21 CH₃ Cl H CH₃ CH₃ B-22 CF₃ Cl H CH₃ CH₃ B-23 OCH₃ Cl H CH₃CH₃ B-24 OCF₃ Cl H CH₃ CH₃ B-25 H CH₃ H CH₃ CH₃ B-26 F CH₃ H CH₃ CH₃B-27 Cl CH₃ H CH₃ CH₃ B-28 Br CH₃ H CH₃ CH₃ B-29 CH₃ CH₃ H CH₃ CH₃ B-30CF₃ CH₃ H CH₃ CH₃ B-31 OCH₃ CH₃ H CH₃ CH₃ B-32 OCF₃ CH₃ H CH₃ CH₃ B-33 HCH₃ CH₃ CH₃ CH₃ B-34 F CH₃ CH₃ CH₃ CH₃ B-35 Cl CH₃ CH₃ CH₃ CH₃ B-36 BrCH₃ CH₃ CH₃ CH₃ B-37 CH₃ CH₃ CH₃ CH₃ CH₃ B-38 CF₃ CH₃ CH₃ CH₃ CH₃ B-39OCH₃ CH₃ CH₃ CH₃ CH₃ B-40 OCF₃ CH₃ CH₃ CH₃ CH₃ B-41 H H H CH₃ CH₂CH₃B-42 F H H CH₃ CH₂CH₃ B-43 Cl H H CH₃ CH₂CH₃ B-44 Br H H CH₃ CH₂CH₃ B-45CH₃ H H CH₃ CH₂CH₃ B-46 CF₃ H H CH₃ CH₂CH₃ B-47 OCH₃ H H CH₃ CH₂CH₃ B-48OCF₃ H H CH₃ CH₂CH₃ B-49 H F H CH₃ CH₂CH₃ B-50 F F H CH₃ CH₂CH₃ B-51 ClF H CH₃ CH₂CH₃ B-52 Br F H CH₃ CH₂CH₃ B-53 CH₃ F H CH₃ CH₂CH₃ B-54 CF₃ FH CH₃ CH₂CH₃ B-55 OCH₃ F H CH₃ CH₂CH₃ B-56 OCF₃ F H CH₃ CH₂CH₃ B-57 H ClH CH₃ CH₂CH₃ B-58 F Cl H CH₃ CH₂CH₃ B-59 Cl Cl H CH₃ CH₂CH₃ B-60 Br Cl HCH₃ CH₂CH₃ B-61 CH₃ Cl H CH₃ CH₂CH₃ B-62 CF₃ Cl H CH₃ CH₂CH₃ B-63 OCH₃Cl H CH₃ CH₂CH₃ B-64 OCF₃ Cl H CH₃ CH₂CH₃ B-65 H CH₃ H CH₃ CH₂CH₃ B-66 FCH₃ H CH₃ CH₂CH₃ B-67 Cl CH₃ H CH₃ CH₂CH₃ B-68 Br CH₃ H CH₃ CH₂CH₃ B-69CH₃ CH₃ H CH₃ CH₂CH₃ B-70 CF₃ CH₃ H CH₃ CH₂CH₃ B-71 OCH₃ CH₃ H CH₃CH₂CH₃ B-72 OCF₃ CH₃ H CH₃ CH₂CH₃ B-73 H CH₃ CH₃ CH₃ CH₂CH₃ B-74 F CH₃CH₃ CH₃ CH₂CH₃ B-75 Cl CH₃ CH₃ CH₃ CH₂CH₃ B-76 Br CH₃ CH₃ CH₃ CH₂CH₃B-77 CH₃ CH₃ CH₃ CH₃ CH₂CH₃ B-78 CF₃ CH₃ CH₃ CH₃ CH₂CH₃ B-79 OCH₃ CH₃CH₃ CH₃ CH₂CH₃ B-80 OCF₃ CH₃ CH₃ CH₃ CH₂CH₃ B-81 H H H CH₃ CF₃ B-82 F HH CH₃ CF₃ B-83 Cl H H CH₃ CF₃ B-84 Br H H CH₃ CF₃ B-85 CH₃ H H CH₃ CF₃B-86 CF₃ H H CH₃ CF₃ B-87 OCH₃ H H CH₃ CF₃ B-88 OCF₃ H H CH₃ CF₃ B-89 HF H CH₃ CF₃ B-90 F F H CH₃ CF₃ B-91 Cl F H CH₃ CF₃ B-92 Br F H CH₃ CF₃B-93 CH₃ F H CH₃ CF₃ B-94 CF₃ F H CH₃ CF₃ B-95 OCH₃ F H CH₃ CF₃ B-96OCF₃ F H CH₃ CF₃ B-97 H Cl H CH₃ CF₃ B-98 F Cl H CH₃ CF₃ B-99 Cl Cl HCH₃ CF₃ B-100 Br Cl H CH₃ CF₃ B-101 CH₃ Cl H CH₃ CF₃ B-102 CF₃ Cl H CH₃CF₃ B-103 OCH₃ Cl H CH₃ CF₃ B-104 OCF₃ Cl H CH₃ CF₃ B-105 H CH₃ H CH₃CF₃ B-106 F CH₃ H CH₃ CF₃ B-107 Cl CH₃ H CH₃ CF₃ B-108 Br CH₃ H CH₃ CF₃B-109 CH₃ CH₃ H CH₃ CF₃ B-110 CF₃ CH₃ H CH₃ CF₃ B-111 OCH₃ CH₃ H CH₃ CF₃B-112 OCF₃ CH₃ H CH₃ CF₃ B-113 H CH₃ CH₃ CH₃ CF₃ B-114 F CH₃ CH₃ CH₃ CF₃B-115 Cl CH₃ CH₃ CH₃ CF₃ B-116 Br CH₃ CH₃ CH₃ CF₃ B-117 CH₃ CH₃ CH₃ CH₃CF₃ B-118 CF₃ CH₃ CH₃ CH₃ CF₃ B-119 OCH₃ CH₃ CH₃ CH₃ CF₃ B-120 OCF₃ CH₃CH₃ CH₃ CF₃ B-121 H H H CF₃ CF₃ B-122 F H H CF₃ CF₃ B-123 Cl H H CF₃ CF₃B-124 Br H H CF₃ CF₃ B-125 CH₃ H H CF₃ CF₃ B-126 CF₃ H H CF₃ CF₃ B-127OCH₃ H H CF₃ CF₃ B-128 OCF₃ H H CF₃ CF₃ B-129 H F H CF₃ CF₃ B-130 F F HCF₃ CF₃ B-131 Cl F H CF₃ CF₃ B-132 Br F H CF₃ CF₃ B-133 CH₃ F H CF₃ CF₃B-134 CF₃ F H CF₃ CF₃ B-135 OCH₃ F H CF₃ CF₃ B-136 OCF₃ F H CF₃ CF₃B-137 H Cl H CF₃ CF₃ B-138 F Cl H CF₃ CF₃ B-139 Cl Cl H CF₃ CF₃ B-140 BrCl H CF₃ CF₃ B-141 CH₃ Cl H CF₃ CF₃ B-142 CF₃ Cl H CF₃ CF₃ B-143 OCH₃ ClH CF₃ CF₃ B-144 OCF₃ Cl H CF₃ CF₃ B-145 H CH₃ H CF₃ CF₃ B-146 F CH₃ HCF₃ CF₃ B-147 Cl CH₃ H CF₃ CF₃ B-148 Br CH₃ H CF₃ CF₃ B-149 CH₃ CH₃ HCF₃ CF₃ B-150 CF₃ CH₃ H CF₃ CF₃ B-151 OCH₃ CH₃ H CF₃ CF₃ B-152 OCF₃ CH₃H CF₃ CF₃ B-153 H CH₃ CH₃ CF₃ CF₃ B-154 F CH₃ CH₃ CF₃ CF₃ B-155 Cl CH₃CH₃ CF₃ CF₃ B-156 Br CH₃ CH₃ CF₃ CF₃ B-157 CH₃ CH₃ CH₃ CF₃ CF₃ B-158 CF₃CH₃ CH₃ CF₃ CF₃ B-159 OCH₃ CH₃ CH₃ CF₃ CF₃ B-160 OCF₃ CH₃ CH₃ CF₃ CF₃B-161 H H H CH₃ C₆H₅* B-162 F H H CH₃ C₆H₅ B-163 Cl H H CH₃ C₆H₅ B-164Br H H CH₃ C₆H₅ B-165 CH₃ H H CH₃ C₆H₅ B-166 CF₃ H H CH₃ C₆H₅ B-167 OCH₃H H CH₃ C₆H₅ B-168 OCF₃ H H CH₃ C₆H₅ B-169 H F H CH₃ C₆H₅ B-170 F F HCH₃ C₆H₅ B-171 Cl F H CH₃ C₆H₅ B-172 Br F H CH₃ C₆H₅ B-173 CH₃ F H CH₃C₆H₅ B-174 CF₃ F H CH₃ C₆H₅ B-175 OCH₃ F H CH₃ C₆H₅ B-176 OCF₃ F H CH₃C₆H₅ B-177 H Cl H CH₃ C₆H₅ B-178 F Cl H CH₃ C₆H₅ B-179 Cl Cl H CH₃ C₆H₅B-180 Br Cl H CH₃ C₆H₅ B-181 CH₃ Cl H CH₃ C₆H₅ B-182 CF₃ Cl H CH₃ C₆H₅B-183 OCH₃ Cl H CH₃ C₆H₅ B-184 OCF₃ Cl H CH₃ C₆H₅ B-185 H CH₃ H CH₃ C₆H₅B-186 F CH₃ H CH₃ C₆H₅ B-187 Cl CH₃ H CH₃ C₆H₅ B-188 Br CH₃ H CH₃ C₆H₅B-189 CH₃ CH₃ H CH₃ C₆H₅ B-190 CF₃ CH₃ H CH₃ C₆H₅ B-191 OCH₃ CH₃ H CH₃C₆H₅ B-192 OCF₃ CH₃ H CH₃ C₆H₅ B-193 H CH₃ CH₃ CH₃ C₆H₅ B-194 F CH₃ CH₃CH₃ C₆H₅ B-195 Cl CH₃ CH₃ CH₃ C₆H₅ B-196 Br CH₃ CH₃ CH₃ C₆H₅ B-197 CH₃CH₃ CH₃ CH₃ C₆H₅ B-198 CF₃ CH₃ CH₃ CH₃ C₆H₅ B-199 OCH₃ CH₃ CH₃ CH₃ C₆H₅B-200 OCF₃ CH₃ CH₃ CH₃ C₆H₅ B-201 H H H —(CH₂)₂— B-202 F H H —(CH₂)₂—B-203 Cl H H —(CH₂)₂— B-204 Br H H —(CH₂)₂— B-205 CH₃ H H —(CH₂)₂— B-206CF₃ H H —(CH₂)₂— B-207 OCH₃ H H —(CH₂)₂— B-208 OCF₃ H H —(CH₂)₂— B-209 HF H —(CH₂)₂— B-210 F F H —(CH₂)₂— B-211 Cl F H —(CH₂)₂— B-212 Br F H—(CH₂)₂— B-213 CH₃ F H —(CH₂)₂— B-214 CF₃ F H —(CH₂)₂— B-215 OCH₃ F H—(CH₂)₂— B-216 OCF₃ F H —(CH₂)₂— B-217 H Cl H —(CH₂)₂— B-218 F Cl H—(CH₂)₂— B-219 Cl Cl H —(CH₂)₂— B-220 Br Cl H —(CH₂)₂— B-221 CH₃ Cl H—(CH₂)₂— B-222 CF₃ Cl H —(CH₂)₂— B-223 OCH₃ Cl H —(CH₂)₂— B-224 OCF₃ ClH —(CH₂)₂— B-225 H CH₃ H —(CH₂)₂— B-226 F CH₃ H —(CH₂)₂— B-227 Cl CH₃ H—(CH₂)₂— B-228 Br CH₃ H —(CH₂)₂— B-229 CH₃ CH₃ H —(CH₂)₂— B-230 CF₃ CH₃H —(CH₂)₂— B-231 OCH₃ CH₃ H —(CH₂)₂— B-232 OCF₃ CH₃ H —(CH₂)₂— B-233 HCH₃ CH₃ —(CH₂)₂— B-234 F CH₃ CH₃ —(CH₂)₂— B-235 Cl CH₃ CH₃ —(CH₂)₂—B-236 Br CH₃ CH₃ —(CH₂)₂— B-237 CH₃ CH₃ CH₃ —(CH₂)₂— B-238 CF₃ CH₃ CH₃—(CH₂)₂— B-239 OCH₃ CH₃ CH₃ —(CH₂)₂— B-240 OCF₃ CH₃ CH₃ —(CH₂)₂— B-241 HH H —(CH₂)₃— B-242 F H H —(CH₂)₃— B-243 Cl H H —(CH₂)₃— B-244 Br H H—(CH₂)₃— B-245 CH₃ H H —(CH₂)₃— B-246 CF₃ H H —(CH₂)₃— B-247 OCH₃ H H—(CH₂)₃— B-248 OCF₃ H H —(CH₂)₃— B-249 H F H —(CH₂)₃— B-250 F F H—(CH₂)₃— B-251 Cl F H —(CH₂)₃— B-252 Br F H —(CH₂)₃— B-253 CH₃ F H—(CH₂)₃— B-254 CF₃ F H —(CH₂)₃— B-255 OCH₃ F H —(CH₂)₃— B-256 OCF₃ F H—(CH₂)₃— B-257 H Cl H —(CH₂)₃— B-258 F Cl H —(CH₂)₃— B-259 Cl Cl H—(CH₂)₃— B-260 Br Cl H —(CH₂)₃— B-261 CH₃ Cl H —(CH₂)₃— B-262 CF₃ Cl H—(CH₂)₃— B-263 OCH₃ Cl H —(CH₂)₃— B-264 OCF₃ Cl H —(CH₂)₃— B-265 H CH₃ H—(CH₂)₃— B-266 F CH₃ H —(CH₂)₃— B-267 Cl CH₃ H —(CH₂)₃— B-268 Br CH₃ H—(CH₂)₃— B-269 CH₃ CH₃ H —(CH₂)₃— B-270 CF₃ CH₃ H —(CH₂)₃— B-271 OCH₃CH₃ H —(CH₂)₃— B-272 OCF₃ CH₃ H —(CH₂)₃— B-273 H CH₃ CH₃ —(CH₂)₃— B-274F CH₃ CH₃ —(CH₂)₃— B-275 Cl CH₃ CH₃ —(CH₂)₃— B-276 Br CH₃ CH₃ —(CH₂)₃—B-277 CH₃ CH₃ CH₃ —(CH₂)₃— B-278 CF₃ CH₃ CH₃ —(CH₂)₃— B-279 OCH₃ CH₃ CH₃—(CH₂)₃— B-280 OCF₃ CH₃ CH₃ —(CH₂)₃— B-281 H H H —(CH₂)₄— B-282 F H H—(CH₂)₄— B-283 Cl H H —(CH₂)₄— B-284 Br H H —(CH₂)₄— B-285 CH₃ H H—(CH₂)₄— B-286 CF₃ H H —(CH₂)₄— B-287 OCH₃ H H —(CH₂)₄— B-288 OCF₃ H H—(CH₂)₄— B-289 H F H —(CH₂)₄— B-290 F F H —(CH₂)₄— B-291 Cl F H —(CH₂)₄—B-292 Br F H —(CH₂)₄— B-293 CH₃ F H —(CH₂)₄— B-294 CF₃ F H —(CH₂)₄—B-295 OCH₃ F H —(CH₂)₄— B-296 OCF₃ F H —(CH₂)₄— B-297 H Cl H —(CH₂)₄—B-298 F Cl H —(CH₂)₄— B-299 Cl Cl H —(CH₂)₄— B-300 Br Cl H —(CH₂)₄—B-301 CH₃ Cl H —(CH₂)₄— B-302 CF₃ Cl H —(CH₂)₄— B-303 OCH₃ Cl H —(CH₂)₄—B-304 OCF₃ Cl H —(CH₂)₄— B-305 H CH₃ H —(CH₂)₄— B-306 F CH₃ H —(CH₂)₄—B-307 Cl CH₃ H —(CH₂)₄— B-308 Br CH₃ H —(CH₂)₄— B-309 CH₃ CH₃ H —(CH₂)₄—B-310 CF₃ CH₃ H —(CH₂)₄— B-311 OCH₃ CH₃ H —(CH₂)₄— B-312 OCF₃ CH₃ H—(CH₂)₄— B-313 H CH₃ CH₃ —(CH₂)₄— B-314 F CH₃ CH₃ —(CH₂)₄— B-315 Cl CH₃CH₃ —(CH₂)₄— B-316 Br CH₃ CH₃ —(CH₂)₄— B-317 CH₃ CH₃ CH₃ —(CH₂)₄— B-318CF₃ CH₃ CH₃ —(CH₂)₄— B-319 OCH₃ CH₃ CH₃ —(CH₂)₄— B-320 OCF₃ CH₃ CH₃—(CH₂)₄— B-321 H H H —(CH₂)₅— B-322 F H H —(CH₂)₅— B-323 Cl H H —(CH₂)₅—B-324 Br H H —(CH₂)₅— B-325 CH₃ H H —(CH₂)₅— B-326 CF₃ H H —(CH₂)₅—B-327 OCH₃ H H —(CH₂)₅— B-328 OCF₃ H H —(CH₂)₅— B-329 H F H —(CH₂)₅—B-330 F F H —(CH₂)₅— B-331 Cl F H —(CH₂)₅— B-332 Br F H —(CH₂)₅— B-333CH₃ F H —(CH₂)₅— B-334 CF₃ F H —(CH₂)₅— B-335 OCH₃ F H —(CH₂)₅— B-336OCF₃ F H —(CH₂)₅— B-337 H Cl H —(CH₂)₅— B-338 F Cl H —(CH₂)₅— B-339 ClCl H —(CH₂)₅— B-340 Br Cl H —(CH₂)₅— B-341 CH₃ Cl H —(CH₂)₅— B-342 CF₃Cl H —(CH₂)₅— B-343 OCH₃ Cl H —(CH₂)₅— B-344 OCF₃ Cl H —(CH₂)₅— B-345 HCH₃ H —(CH₂)₅— B-346 F CH₃ H —(CH₂)₅— B-347 Cl CH₃ H —(CH₂)₅— B-348 BrCH₃ H —(CH₂)₅— B-349 CH₃ CH₃ H —(CH₂)₅— B-350 CF₃ CH₃ H —(CH₂)₅— B-351OCH₃ CH₃ H —(CH₂)₅— B-352 OCF₃ CH₃ H —(CH₂)₅— B-353 H CH₃ CH₃ —(CH₂)₅—B-354 F CH₃ CH₃ —(CH₂)₅— B-355 Cl CH₃ CH₃ —(CH₂)₅— B-356 Br CH₃ CH₃—(CH₂)₅— B-357 CH₃ CH₃ CH₃ —(CH₂)₅— B-358 CF₃ CH₃ CH₃ —(CH₂)₅— B-359OCH₃ CH₃ CH₃ —(CH₂)₅— B-360 OCF₃ CH₃ CH₃ —(CH₂)₅— B-361 H H H —(CH₂)₆—B-362 F H H —(CH₂)₆— B-363 Cl H H —(CH₂)₆— B-364 Br H H —(CH₂)₆— B-365CH₃ H H —(CH₂)₆— B-366 CF₃ H H —(CH₂)₆— B-367 OCH₃ H H —(CH₂)₆— B-368OCF₃ H H —(CH₂)₆— B-369 H F H —(CH₂)₆— B-370 F F H —(CH₂)₆— B-371 Cl F H—(CH₂)₆— B-372 Br F H —(CH₂)₆— B-373 CH₃ F H —(CH₂)₆— B-374 CF₃ F H—(CH₂)₆— B-375 OCH₃ F H —(CH₂)₆— B-376 OCF₃ F H —(CH₂)₆— B-377 H Cl H—(CH₂)₆— B-378 F Cl H —(CH₂)₆— B-379 Cl Cl H —(CH₂)₆— B-380 Br Cl H—(CH₂)₆— B-381 CH₃ Cl H —(CH₂)₆— B-382 CF₃ Cl H —(CH₂)₆— B-383 OCH₃ Cl H—(CH₂)₆— B-384 OCF₃ Cl H —(CH₂)₆— B-385 H CH₃ H —(CH₂)₆— B-386 F CH₃ H—(CH₂)₆— B-387 Cl CH₃ H —(CH₂)₆— B-388 Br CH₃ H —(CH₂)₆— B-389 CH₃ CH₃ H—(CH₂)₆— B-390 CF₃ CH₃ H —(CH₂)₆— B-391 OCH₃ CH₃ H —(CH₂)₆— B-392 OCF₃CH₃ H —(CH₂)₆— B-393 H CH₃ CH₃ —(CH₂)₆— B-394 F CH₃ CH₃ —(CH₂)₆— B-395Cl CH₃ CH₃ —(CH₂)₆— B-396 Br CH₃ CH₃ —(CH₂)₆— B-397 CH₃ CH₃ CH₃ —(CH₂)₆—B-398 CF₃ CH₃ CH₃ —(CH₂)₆— B-399 OCH₃ CH₃ CH₃ —(CH₂)₆— B-400 OCF₃ CH₃CH₃ —(CH₂)₆— B-401 H H H —CH═CH—CH₂—CH₂— B-402 F H H —CH═CH—CH₂—CH₂—B-403 Cl H H —CH═CH—CH₂—CH₂— B-404 Br H H —CH═CH—CH₂—CH₂— B-405 CH₃ H H—CH═CH—CH₂—CH₂— B-406 CF₃ H H —CH═CH—CH₂—CH₂— B-407 OCH₃ H H—CH═CH—CH₂—CH₂— B-408 OCF₃ H H —CH═CH—CH₂—CH₂— B-409 H F H—CH═CH—CH₂—CH₂— B-410 F F H —CH═CH—CH₂—CH₂— B-411 Cl F H —CH═CH—CH₂—CH₂—B-412 Br F H —CH═CH—CH₂—CH₂— B-413 CH₃ F H —CH═CH—CH₂—CH₂— B-414 CF₃ F H—CH═CH—CH₂—CH₂— B-415 OCH₃ F H —CH═CH—CH₂—CH₂— B-416 OCF₃ F H—CH═CH—CH₂—CH₂— B-417 H Cl H —CH═CH—CH₂—CH₂— B-418 F Cl H—CH═CH—CH₂—CH₂— B-419 Cl Cl H —CH═CH—CH₂—CH₂— B-420 Br Cl H—CH═CH—CH₂—CH₂— B-421 CH₃ Cl H —CH═CH—CH₂—CH₂— B-422 CF₃ Cl H—CH═CH—CH₂—CH₂— B-423 OCH₃ Cl H —CH═CH—CH₂—CH₂— B-424 OCF₃ Cl H—CH═CH—CH₂—CH₂— B-425 H CH₃ H —CH═CH—CH₂—CH₂— B-426 F CH₃ H—CH═CH—CH₂—CH₂— B-427 Cl CH₃ H —CH═CH—CH₂—CH₂— B-428 Br CH₃ H—CH═CH—CH₂—CH₂— B-429 CH₃ CH₃ H —CH═CH—CH₂—CH₂— B-430 CF₃ CH₃ H—CH═CH—CH₂—CH₂— B-431 OCH₃ CH₃ H —CH═CH—CH₂—CH₂— B-432 OCF₃ CH₃ H—CH═CH—CH₂—CH₂— B-433 H CH₃ CH₃ —CH═CH—CH₂—CH₂— B-434 F CH₃ CH₃—CH═CH—CH₂—CH₂— B-435 Cl CH₃ CH₃ —CH═CH—CH₂—CH₂— B-436 Br CH₃ CH₃—CH═CH—CH₂—CH₂— B-437 CH₃ CH₃ CH₃ —CH═CH—CH₂—CH₂— B-438 CF₃ CH₃ CH₃—CH═CH—CH₂—CH₂— B-439 OCH₃ CH₃ CH₃ —CH═CH—CH₂—CH₂— B-440 OCF₃ CH₃ CH₃—CH═CH—CH₂—CH₂— B-441 H H —(CH₂)₃— CH₃ B-442 F H —(CH₂)₃— CH₃ B-443 Cl H—(CH₂)₃— CH₃ B-444 Br H —(CH₂)₃— CH₃ B-445 CH₃ H —(CH₂)₃— CH₃ B-446 CF₃H —(CH₂)₃— CH₃ B-447 OCH₃ H —(CH₂)₃— CH₃ B-448 OCF₃ H —(CH₂)₃— CH₃ B-449H D —(CH₂)₃— CH₃ B-450 F D —(CH₂)₃— CH₃ B-451 Cl D —(CH₂)₃— CH₃ B-452 BrD —(CH₂)₃— CH₃ B-453 CH₃ D —(CH₂)₃— CH₃ B-454 CF₃ D —(CH₂)₃— CH₃ B-455OCH₃ D —(CH₂)₃— CH₃ B-456 OCF₃ D —(CH₂)₃— CH₃ B-457 H H —(CH₂)₃— D B-458F H —(CH₂)₃— D B-459 Cl H —(CH₂)₃— D B-460 Br H —(CH₂)₃— D B-461 CH₃ H—(CH₂)₃— D B-462 CF₃ H —(CH₂)₃— D B-463 OCH₃ H —(CH₂)₃— D B-464 OCF₃ H—(CH₂)₃— D B-465 H D —(CH₂)₃— D B-466 F D —(CH₂)₃— D B-467 Cl D —(CH₂)₃—D B-468 Br D —(CH₂)₃— D B-469 CH₃ D —(CH₂)₃— D B-470 CF₃ D —(CH₂)₃— DB-471 OCH₃ D —(CH₂)₃— D B-472 OCF₃ D —(CH₂)₃— D B-473 H H —(CH₂)₄— CH₃B-474 F H —(CH₂)₄— CH₃ B-475 Cl H —(CH₂)₄— CH₃ B-476 Br H —(CH₂)₄— CH₃B-477 CH₃ H —(CH₂)₄— CH₃ B-478 CF₃ H —(CH₂)₄— CH₃ B-479 OCH₃ H —(CH₂)₄—CH₃ B-480 OCF₃ H —(CH₂)₄— CH₃ B-481 H D —(CH₂)₄— CH₃ B-482 F D —(CH₂)₄—CH₃ B-483 Cl D —(CH₂)₄— CH₃ B-484 Br D —(CH₂)₄— CH₃ B-485 CH₃ D —(CH₂)₄—CH₃ B-486 CF₃ D —(CH₂)₄— CH₃ B-487 OCH₃ D —(CH₂)₄— CH₃ B-488 OCF₃ D—(CH₂)₄— CH₃ B-489 H H —(CH₂)₄— D B-490 F H —(CH₂)₄— D B-491 Cl H—(CH₂)₄— D B-492 Br H —(CH₂)₄— D B-493 CH₃ H —(CH₂)₄— D B-494 CF₃ H—(CH₂)₄— D B-495 OCH₃ H —(CH₂)₄— D B-496 OCF₃ H —(CH₂)₄— D B-497 H D—(CH₂)₄— D B-498 F D —(CH₂)₄— D B-499 Cl D —(CH₂)₄— D B-500 Br D—(CH₂)₄— D B-501 CH₃ D —(CH₂)₄— D B-502 CF₃ D —(CH₂)₄— D B-503 OCH₃ D—(CH₂)₄— D B-504 OCF₃ D —(CH₂)₄— D *C₆H₅ = phenyl

The compounds of the present invention can be prepared by using routinetechniques familiar to a skilled person. In particular, the compounds ofthe formula I can be prepared according to the following schemes,wherein the variables, if not stated otherwise, are as defined above.

Compounds of formula I wherein X is CR⁷R⁸ and R^(5b) is H (=compoundsI′) can be synthesized as described in scheme 1 below. The protectedtetrahydrobenzodiazepine or tetrahydroquinoxaline 1, wherein Z is ahydrogen or a halogen atom, such as Cl, Br or I and PG is a commonprotective group, such as a carbamate, especially boc, is acylated withthe acrylic acid derivative 2, wherein LG is an appropriate leavinggroup, such as Cl or an anhydride or a chloroformate, in the presence ofa base, such as triethylamine or Hünig's base, in an organic solvent,such as ether or methylene chloride. Reaction of 3 with a Lewis acid ora Brönstedt acid HA or irradiation with a suitable wavelength commonlyderived from a mercury lamp in an adequate solvent, such as acetone ortoluene, in a common photoreactor yields cyclization to 4. Reduction ofthe carbonyl group with common reduction agents like borohydrides suchas sodium borohydride or borane-tetrahydrofurane-complex yields 5, whichis deprotected using suitable reagents such as strong bases or acids toI′, wherein R^(4a) and R^(4b) and R^(5b) are H. Compounds I whereinR^(4a) and R^(4b) form together ═O can be obtained by skipping thereduction step to 5 and deprotecting 4.

If desired, substituents R¹ different from hydrogen can be introducedfor example via alkylation under typical conditions such as stirring inan appropriate solvent in the presence of an alkylhalide and a base orvia other common substitution reactions.

Compounds I wherein R^(5b) is different from H can be prepared, forexample, by reacting compound 4 with a compound LG-R^(5b) in thepresence of a base, wherein LG is an appropriate leaving group, such asCl or Br.

Compounds I wherein R^(5b) is different from H and R⁸ is CH₃ (=compoundsI″) can be prepared, for example, as out lined in scheme 2 below.Acylation of 1 with the allylic acid derivative 6, wherein LG is anappropriate leaving group, such as Cl or an anhydride or achloroformate, in the presence of a base, such as triethylamine orHünig's base, in an organic solvent, such as ether or methylenechloride, yields 7, which is reacted in a Heck-type reaction, e.g.employing palladium acetate in the presence of a base, such as potassiumcarbonate, to yield the cyclization product 8. Reduction of the carbonylgroup with common reduction agents like borohydrides such as sodiumborohydride or borane-tetrahydrofurane-complex yields 9, which isdeprotected using suitable reagents such as strong bases or acids to I″,wherein R^(4a) and R^(4b) are H. Compounds I wherein R^(4a) and R^(4b)form together ═O can be obtained by skipping the reduction step to 9 anddeprotecting 8. If desired, substituents R¹ different from hydrogen canbe introduced for example via alkylation under typical conditions suchas stirring in an appropriate solvent in the presence of an alkylhalideand a base or via other common substitution reactions.

Compounds I wherein X is NR⁶ (=compounds I′″) can be prepared asoutlined in scheme 3 below. Acylation of 1 with the β-amino acidderivative 10, wherein PG′ is a protection group different from PG andLG is an appropriate leaving group, such as Cl or an anhydride or achloroformate, in the presence of a base, such as triethylamine orHünig's base, in an organic solvent, such as ether or methylenechloride, yields 11. This is first selectively deprotected at the aminogroup NR⁶PG′. The partially deprotected compound is then reacted in acyclization reaction to 12 under Buchwald-Hartwig reaction conditionssuch as the use of a Pd catalyst, e.g. tetrakis(triphenylphosphine)palladium in the presence of as base, such as sodium tert-butylate andpotassium carbonate. Reduction of the carbonyl group of 12 with commonreduction agents like borohydrides such as sodium borohydride orborane-tetrahydrofurane-complex yields 13, which is deprotected usingsuitable reagents such as strong bases or acids to I′″, wherein R^(4a)and R^(4b) are H. Compounds I wherein R^(4a) and R^(4b) form together ═Ocan be obtained by skipping the reduction step to 13 and deprotecting12. If desired, substituents R¹ different from hydrogen can beintroduced for example via alkylation under typical conditions such asstirring in an appropriate solvent in the presence of an alkylhalide anda base or via other common substitution reactions.

Alternatively to the method depicted in scheme 1, compounds I wherein Xis CR⁷R⁸ and R^(5b) is H (=compounds I′) can be synthesized as describedin scheme 4 below. Readily available anilines 14 are derivatized withcarbonyl moieties 15 by acylation procedures employing appropriateleaving groups LG, such as chlorides or anhydrides, in the presence of abase such as triethylamine or Hünig's base, in an organic solvent, suchas diethyl ether or methylene chloride to yield 16. Cyclization products17 are received by irradiation with a suitable wavelength commonlyderived from a mercury lamp in an adequate solvent such as acetone ortoluene in a common photoreactor known to those skilled in the art.Reduction with common reduction agents like borohydrides such as sodiumborohydride or borane-tetrahydrofurane-complex yield suitableintermediates 18 that are alkylated with alkylamides 19 employingsuitable leaving groups LG such as chlorides or bromides. Afterreduction to the corresponding amines 20 cyclization is performed in asuitable solvent like acetonitrile or methanol at room temperature orhigher temperature by addition of an acid and substituted ketones oraldehydes to obtain compounds I′.

Alternatively to the method depicted in scheme 3, compounds I wherein Xis NR⁶ (=compounds I′″) can be prepared as outlined in scheme 5 below.

Readily available starting materials 22 are alkylated with alkylamides19 employing suitable leaving groups LG such as chlorides or bromides togive 23. After reduction to the corresponding amines 24 cyclization isperformed in a suitable solvent like acetonitrile or methanol at roomtemperature or higher temperature by addition of an acid and substitutedketones or aldehydes 21 to obtain compounds I′″.

Compounds I wherein R^(4a) and R^(4b) are not H or do not form togethera group ═O can be prepared by standard derivatization methods ofcompounds wherein R^(4a) and R^(4b) form together a group ═O. Forinstance, compounds wherein R^(4a) and R^(4b) form together a group ═Smay be prepared by reaction with a sulfurization agent, such asLawesson's reagent or P₂S₅. Alkyl and related groups as radicals R^(4a)and R^(4b) may be introduced via Grignard reduction. Amino and relatedgroups may be introduced via reductive amination. Hydroxyl group R^(4a)or R^(4b) may be introduced by reducing the carbonyl group. This may bealkylated to yield alkoxy and related groups R^(4a) and R^(4b) orsubstituted by diverse groups.

If not otherwise indicated, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example a loweralcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone ormethyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the preparation methods are within routinetechniques.

Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which is hereinincorporated by reference in its entirety. Synthesis of the compounds ofthe invention may be accomplished by methods analogous to thosedescribed in the synthetic schemes described hereinabove and in specificexamples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

Moreover, the present invention relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Additionally, the compounds according to the invention include more ofthe respective isotope than occurs naturally occurs and which is presentin compounds I.

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one additional neutron than the normally abundantisotope of the respective atom. Deuterated compounds have been used inpharmaceutical research to investigate the in vivo metabolic fate of thecompounds by evaluation of the mechanism of action and metabolic pathwayof the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64,3, 367-391 (1975)). Such metabolic studies are important in the designof safe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

Incorporation of a heavy atom, particularly substitution of deuteriumfor hydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pK_(a) and lipid solubility. These changes mayinfluence the fate of the drug at different steps along its passagethrough the body. Absorption, distribution, metabolism or excretion canbe changed. Absorption and distribution are processes that dependprimarily on the molecular size and the lipophilicity of the substance.These effects and alterations can affect the pharmacodynamic response ofthe drug molecule if the isotopic substitution affects a region involvedin a ligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The present invention further relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compound Ias defined above or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, or comprising at least onecompound as defined in any of the preceding claims wherein at least oneof the atoms has been replaced by its stable, non-radioactive isotope,preferably wherein at least one hydrogen atom has been replaced by adeuterium atom, in combination with at least one pharmaceuticallyacceptable carrier and/or auxiliary substance.

The present invention further relates to a compound I as defined aboveor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

The present invention also relates to a compound I as defined above oran N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond tothe modulation of the 5-HT_(2c) receptor.

The present invention also relates to the use of a compound I as definedabove or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2c) receptor, and to a method for treatingdisorders which respond to the modulation of the 5-HT_(2c) receptor,which method comprises administering to a subject in need thereof atleast one compound I as defined above or an N-oxide, a tautomeric form,a stereoisomer or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are modulators of the 5-HT_(2C)receptor. Specifically, the compounds of formula I are agonists orpartial agonists of the 5-HT_(2C) receptor. Thus, in a specificembodiment, the invention relates to a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond to5-HT_(2c) receptor agonists, further to the use of a compound I asdefined above or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to 5-HT_(2c)receptor agonists, and to a method for treating disorders which respondto 5-HT_(2c) receptor agonists, which method comprises administering toa subject in need thereof at least one compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof

Within the meaning of the invention, the term “disorder” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, i.e. anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns, i.e. syndromes, which can betreated in accordance with the invention.

In one aspect of the invention, the diseases to be treated are disordersare damage of the central nervous system, disorders of the centralnervous system, eating disorders, ocular hypertension, cardiovasculardisorders, gastrointestinal disorders and diabetes.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. These are, for example, cognitive dysfunction, attention deficitdisorder/hyperactivity syndrome and cognitive deficits related withschizophrenia, attention deficit/hyperactivity syndrome, personalitydisorders, affective disorders, motion or motor disorders, pain,migraine, sleep disorders (including disturbances of the Circadianrhythm), feeding disorders, diseases associated with neurodegeneration,addiction diseases, obesity or psoriasis.

Examples of cognitive dysfunction are deficits in memory, cognition, andlearning, Alzheimer's disease, age-related cognitive decline, and mildcognitive impairment, or any combinations thereof. Examples ofpersonality disorders are schizophrenia and cognitive deficits relatedto schizophrenia. Examples of affective disorders are depression,anxiety, bipolar disorder and obsessive compulsive disorders, or anycombination thereof. Examples of motion or motor disorders areParkinson's disease and epilepsy. Examples of feeding disorders areobesity, bulimia, weight loss and anorexia, especially anorexia nervosa.Examples of diseases associated with neurodegeneration are stroke,spinal or head trauma, and head injuries, such as hydrocephalus.

Pain condition includes nociceptive pain, neuropathic pain or acombination thereof. Such pain conditions or disorders can include, butare not limited to, postoperative pain, osteoarthritis pain, pain due toinflammation, rheumatoid arthritis pain, musculoskeletal pain, burn pain(including sunburn), ocular pain, the pain associated with dentalconditions (such as dental caries and gingivitis), post-partum pain,bone fracture, herpes, HIV, traumatic nerve injury, stroke,post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complexregional pain syndrome, spinal cord injury, sciatica, phantom limb pain,diabetic neuropathy, hyperalgesia and cancer.

In certain other embodiments, the disease condition is bladderdysfunction, including urinary incontinence.

Diabetes includes diabetes insipidus, diabetes mellitus, type Idiabetes, type II diabetes, type III diabetes, diabetes secondary topancreatic diseases, diabetes related to steroid use, diabetescomplications, hyperglycemia and insulin resistance.

The addiction diseases include psychiatric disorders and behavioraldisturbances which are caused by the abuse of psychotropic substances,such as pharmaceuticals or narcotics, and also other addiction diseases,such as addiction to gaming (impulse control disorders not elsewhereclassified). Examples of addictive substances are: opioids (e.g.morphine, heroin and codeine), cocaine; nicotine; alcohol; substanceswhich interact with the GABA chloride channel complex, sedatives,hypnotics and tranquilizers, for example benzodiazepines; LSD;cannabinoids; psychomotor stimulants, such as3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine andamphetamine-like substances such as methylphenidate, other stimulantsincluding caffeine and nicotine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, nicotine and alcohol. Especially, addictiondisorders include alcohol abuse, cocaine abuse, tobacco abuse andsmoking cessation.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the invention of theformula (I) which themselves do not possess any psychotropic effect.This can also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine.

Examples of gastrointestinal disorders are irritable bowel syndrome.

Preferably, the disorders are selected from the group consisting ofbipolar disorder, depression, atypical depression, mood episodes,adjustment disorders, anxiety, panic disorders, post-traumatic syndrome,psychoses, schizophrenia, cognitive deficits of schizophrenia, memoryloss, dementia of aging, Alzheimer's disease, behavioral disordersassociated with dementia, social phobia, mental disorders in childhood,attention deficit hyperactivity disorder, organic mental disorders,autism, mutism, disruptive behavior disorder, impulse control disorder,borderline personality disorder, obsessive compulsive disorder, migraineand other conditions associated with cephalic pain or other pain, raisedintracranial pressure, seizure disorders, epilepsy, substance usedisorders, alcohol abuse, cocaine abuse, tobacco abuse, smokingcessation, sexual dysfunction/erectile dysfunction in males, sexualdysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, spinal cordinjury, trauma, stroke, pain, bladder dysfunction/urinary incontinence,encephalitis, meningitis, eating disorders, obesity, bulimia, weightloss, anorexia nervosa, ocular hypertension, cardiovascular disorders,gastrointestinal disorders, diabetes insipidus, diabetes mellitus, typeI diabetes, type II diabetes, type III diabetes, diabetes secondary topancreatic diseases, diabetes related to steroid use, diabetescomplications, hyperglycemia and insulin resistance, and arespecifically schizophrenia, depression, bipolar disorders, obesity orsubstance use disorders.

The compounds of the invention may be used for a preventive treatment(prophylaxis), in particular as relapse prophylaxis or phaseprophylaxis, but are preferably used for a treatment in its propersense, i.e. for the treatment of acute or chronic signs, symptoms and/ormalfunctions. The treatment can be orientated symptomatically, forexample as the suppression of symptoms. It can be effected over a shortperiod, be orientated over the medium term or can be a long-termtreatment, for example within the context of a maintenance therapy.

In another embodiment, the present invention relates to the use of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing (the development of) a disease condition asdescribed above and to a method for preventing (the development of) adisease condition as described above comprises administering to thesubject in need of treatment thereof (e.g., a mammal, such as a human) atherapeutically effective amount of a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof. As used herein, the term “prevent” a diseasecondition by administration of any of the compounds described hereinmeans that the detectable physical characteristics or symptoms of thedisease or condition do not develop following the administration of thecompound described herein. Alternatively, the method comprisesadministering to the subject a therapeutically effective amount of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of at least onecognitive enhancing drug.

In yet another embodiment, the present invention relates to the use acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing the progression (e.g., worsening) of adisease condition and to a method for preventing the progression (e.g.,worsening) of a disease condition, which method comprises administeringto the subject in need of treatment thereof (e.g., a mammal, such as ahuman) a therapeutically effective amount of a compound I as definedabove or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof

There are several lines of evidence suggesting that 5-HT_(2C) agonistsor partial agonists would have therapeutic use in a variety of diseases,disorders and conditions.

Knockout mice models lacking the 5-HT_(2C) receptor exhibit hyperphagia,obesity and are more prone to seizures and sudden death [Tecott L H, SunL M, Akana S F, Strack A M, Lowenstein D H, Dallman M F, Julius D (1995)Eating disorder and epilepsy in mice lacking 5-HT_(2C) serotoninreceptors. Nature 374:542-546]. They also exhibit compulsive-likebehavior [Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003).Compulsive behavior in the 5-HT_(2C) receptor knockout mouse. Phys.Behay. 78:641-649], hyperresponsiveness to repeated stress [Chou-Green JM, Holscher T D, Dallman M F, Akana S F (2003). Repeated stress in youngand old 5-HT_(2C) receptor knockout mouse. Phys. Behay. 79:217-226],wakefulness [Frank M G, Stryker M P, Tecott L H (2002). Sleep and sleephomeostasis in mice lacking the 5-HT_(2C) receptor.Neuropsychopharmacology 27:869-873], hyperactivity and drug dependence[Rocha B A, Goulding E H, O'Dell L E, Mead A N, Coufal N G, Parsons L H,Tecott L H (2002). Enhanced locomotor, reinforcing and neurochemicaleffects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutantmice. J. Neurosci. 22:10039-10045].

5-HT_(2C) is unique among other G-protein-coupled receptors (GPCRs) inthat its pre-mRNA is a substrate for base modification via hydrolyticdeamination of adenosines to yield inosines. Five adenosines, locatedwithin a sequence encoding the putative second intracellular domain canbe converted to inosines. This editing can alter the coding potential ofthe triplet codons and allows for the generation of multiple differentreceptor isoforms. The edited receptor isoforms were shown to havereduced ability to interact with G-proteins in the absence of agoniststimulation [Werry, T D, Loiacono R, Sexton P A, Christopoulos A (2008).RNA editing of the serotonin 5-HT_(2C) receptor and its effects on cellsignaling, pharmacology and brain function. Pharmac. Therap. 119:7-23].

Edited 5-HT_(2C) isoforms with reduced function are significantlyexpressed in the brains of depressed suicide victims [Schmauss C (2003)Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing.Neuroscientist 9:237-242. Iwamoto K, Kato T (2003). RNA editing ofserotonin 2C receptor in human postmortem brains of major mentaldisorders. Neurosci. Lett. 346:169-172] and in the learned helplessnessrats (a well established animal model of depression) [Iwamotoa K,Nakatanib N, Bundoa M, Yoshikawab T, Katoa T (2005). Altered RNA editingof serotonin 2C receptor in a rat model of depression. Neurosci. Res.53:69-76] suggesting a link between 5-HT_(2C) function and depression.There are also implications of edited 5-HT_(2C) isoforms and spatialmemory [Du Y, Stasko M, Costa A C, Davissone M T, Gardiner K J (2007).Editing of the serotonin 2C receptor pre-mRNA Effects of the MorrisWater Maze. Gene 391:186-197]. In addition, fully edited isoforms of thehuman 5-HT_(2C) receptor display a striking reduction in sensitivity tolysergic acid diethylamide (LSD) and to atypical antipsychotic drugsclozapine and loxapine, suggesting a possible role of the receptor inthe etiology and pharmacology of schizophrenia [Niswender C M,Herrick-Davis K., Dilley G E, Meltzer H Y, Overholser J C, Stockmeier CA, Emeson R B, Sanders-Bush E (2001). RNA Editing of the Human Serotonin5-HT_(2C) Receptor: Alterations in Suicide and Implications forSerotonergic Pharmacotherapy. Neuropsychopharm. 24:478-491].

Recently, the availability of potent and selective 5-HT_(2C) receptoragonists made it possible to directly investigate the effects of5-HT_(2C) agonists and their therapeutic potential. Thus recent studiesdemonstrated that selective 5-HT_(2C) agonists resulted in decreasedfood intake and body weight gain in normal and obese rats [Smith B M, etal. (2008). Discovery and structure-activity relationship of(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin),a selective serotonin 5-HT_(2C) receptor agonist for the treatment ofobesity. J Med Chem 51:305-313. Thomsen W J, Grottick A J, Menzaghi F,Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, ChenW, Al-Shama H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, A NovelSelective Human 5-HT_(2C) Agonist: In Vitro and In Vivo PharmacologicalCharacterization. J Pharmacol Exp Ther. 325:577-587. Rosenzweig-LipsonS, Zhang J, Mazandarani H, Harrison B L, Sabb A, Sabalski J, Stack G,Welmaker G, Barrett J E, Dunlop J (2006) Antiobesity-like effects of the5-HT_(2C) receptor agonist WAY-161503. Brain Res. 1073-1074:240-251.Dunlop J, Sabb A L, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E,Sukoff S, Vogel R L, Stack G, Schechter L, Harrison B L,Rosenzweig-Lipson S (2005). WAY-163909 [97bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],a novel 5-hydroxytryptamine 2C receptor—selective agonist with anorecticactivity. J Pharmacol Exp Ther. 313:862-869.].

Furthermore, selective 5-HT_(2C) receptor agonists produceantidepressant effects in animal models of depression comparable tothose of SSRIs but with a much faster onset of action and a therapeuticwindow that avoids antidepressant-induced sexual dysfunction. Theseagonists were also effective in animal models of compulsive behaviorsuch as scheduled induced polydipsia and they also exhibited decreasedhyperactivity and aggression in rodents [Rosenzweig-Lipson S, Sabb A,Stack G, Mitchell P, Lucki I, Malberg J E, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo S J, Dunlop J, Barrett J E, Marquis K L (2007)Antidepressant-like effects of the novel, selective, 5-HT_(2C) receptoragonist WAY-163909 in rodents. Psychopharmacology (Berlin) 192:159-170.Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_(2C) receptoragonists as an innovative approach for psychiatric disorders. Drug newsPerspect, 20: 565-571. Cryan, J F, Lucki I (2000). Antidepressant-likebehavioral effects mediated by 5-Hydroxytryptamine 2C receptors. J.Pharm. Exp. Ther. 295:1120-1126.].

Acute or chronic administration of 5-HT_(2C) agonists decreases thefiring rate of ventral tegmental area dopamine neurons but not that ofsubstantia nigra. In addition 5-HT_(2C) agonists reduce dopamine levelsin the nucleus accumbens but not in the striatum (the region of thebrain mostly associated with extrapyramidal side effects) [Di Matteo,V., Di Giovanni, G., Di Mascio, M., & Esposito, E. (1999). S B 242084, aselective serotonin 2C receptor antagonist, increases dopaminergictransmission in the mesolimbic system. Neuropharmacology 38, 1195-1205.Di Giovanni, G., Di Matteo, V., Di Mascio, M., & Esposito, E. (2000).Preferential modulation of mesolimbic vs. nigrostriatal dopaminergicfunction by serotonin2C/2B receptor agonists: a combined in vivoelectrophysiological and microdialysis study. Synapse 35, 53-61. MarquisK L, Sabb A L, Logue S F, Brennan J A, Piesla M J, Comery T A, Grauer SM, Ashby C R, Jr., Nguyen H Q, Dawson L A, Barrett J E, Stack G, MeltzerH Y, Harrison B L, Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi] indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonistwith preclinical antipsychotic-like activity. J Pharmacol Exp Ther320:486-496.]. Therefore it is expected that 5-HT_(2C) receptor agonistswill selectively decrease mesolimibic dopamine levels without affectingthe nigrostriatal pathway thus avoiding the EPS side effects of typicalantipsychotics. Several 5-HT_(2C) receptor agonists have shownantipsychotic activity in animal models of schizophrenia without EPSbased on the lack of effect in catalepsy [Marquis K L, Sabb A L, Logue SF, Brennan J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr.,Nguyen H Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L,Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2Creceptor-selective agonist with preclinical antipsychotic-like activity.J Pharmacol Exp Ther 320:486-496. Siuciak J A, Chapin D S, McCarthy S A,Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour P A,Swick A, Iredale P A (2007) CP-809,101, a selective 5-HT_(2C) agonist,shows activity in animal models of antipsychotic activity.Neuropharmacology 52:279-290]. The antipsychotic activity of 5-HT_(2C)receptor agonists without EPS coupled with their beneficial effects inmood disorders and cognition and their antiobesity like effects render5-HT_(2C) receptor agonists as unique agents to treat schizophrenia[Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_(2C) receptoragonists as an innovative approach for psychiatric disorders. Drug newsPerspect, 20: 565-571. Dunlop J, Marquis K L, Lim H K, Leung L, Kao J,Cheesman C, Rosenzweig-Lipson S (2006). Pharmacological profile of the5-HT_(2C) receptor agonist WAY-163909; therapeutic potential in multipleindications. CNS Dug Rev. 12:167-177.].

In addition 5-HT_(2C) modulation has been implicated in epilepsy [IsaacM (2005). Serotonergic 5-HT_(2C) receptors as a potential therapeutictarget for the antiepileptic drugs. Curr. Topics Med. Chem. 5:59:67],psoriasis [Thorslund K, Nordlind K (2007). Serotonergic drugs-a possiblerole in the treatment of psoriasis? Drug News Perspect 20:521-525],Parkinson's disease and related motor disorders [Esposito E, Di MatteoV, Pierucci M, Benigno A, Di Giavanni, G (2007). Role of central5-HT_(2C) receptor in the control of basal ganglia functions. The BasalGanglia Pathophysiology: Recent Advances 97-127], behavioral deficits[Barr A M, Lahmann-Masten V, Paulus M, Gainetdinov R P, Caron M G, GeyerM A (2004). The selective serotonin-2A receptor antagonist M100907reverses behavioral deficits in dopamine transporter knockout mice.Neuropsychopharmacology 29:221-228], anxiety [Dekeyne A, Mannoury laCour C, Gobert A, Brocco M, Lejuene F. Serres F, Sharp T, Daszuta A,Soumier A, Papp M, Rivet J M, Flik G, Cremers T I, Muller O, Lavielle G,Millan M J (2208). 532006, a novel 5-HT_(2C) receptor antagonistsdisplaying broad-based antidepressant and anxiolytic properties inrodent models. Psychopharmacology 199:549-568. Nunes-de-Souza V,Nunes-de-Souza R L, Rodgers R J Canto-de-Souza A (2008). 5-HT2 receptoractivation in the midbrain periaqueductal grey (PAG) reducesanxiety-like behavior in mice. Behav. Brain Res. 187:72-79.], migraine[Leone M, Rigamonti A, D'Amico D, Grazzi L, Usai S, Bussone G (2001).The serotonergic system in migraine. Journal of Headache and Pain2(Suppl. 1):S43-S46], Alzheimer's disease [Arjona A A, Pooler A M, Lee RK, Wurtman R J (2002). Effect of a 5-HT_(2C) serotonin agonist,dexnorfenfluramine, on amyloid precursor protein metabolism in guineapigs. Brain Res. 951:135-140], pain and spinal cord injury [Nakae A,Nakai K, Tanaka T, Hagihira S, Shibata M, Ueda K, Maximo T (2008). Therole of RNA editing of the serotonin 2C receptor in a rat model oforo-facial neuropathic pain. The European Journal of Neuroscience27:2373-2379. Nakae A, Nakai K, Tanaka T, Takashina M, Hagihira S,Shibata M, Ueda K, Mashimo T (2008). Serotonin 2C receptor mRNA editingin neuropathic pain model. Neurosci. Res. 60:228-231. Kao T, Shumsky JS, Jacob-Vadakot S, Timothy H B, Murray M, Moron, K A (2006). Role ofthe 5-HT_(2C) receptor in improving weight-supported stepping in adultrats spinalized as neonates. Brain Res. 1112:159-168.], sexualdysfunction [Motofei I G (2008). A dual physiological character forsexual function: the role of serotonergic receptors. BJU International101:531-534. Shimada I, Maeno K, Kondoh Y, Kaku H, Sugasawa K, Kimura Y,Hatanaka K, Naitou Y. Wanibuchi F, Sakamoto S; Tsukamoto S (2008).Synthesis and structure-activity relationships of a series ofbenzazepine derivatives as 5-HT_(2C) receptor agonists. Bioorg. Med.Chem. 16:3309-3320.], smoking cessation [Fletcher P J, Le A L), HigginsG A (2008). Serotonin receptors as potential targets for modulation ofnicotine use and dependence. Progress Brain Res. 172:361-83], substancedependence [Bubar M J, Cunningham K A (2008). Prospects for serotonin5-HT2R pharmacotherapy in psychostimulant abuse. Progress Brain Res.172:319-46], and ocular hypertension [Sharif N A, McLaughlin M A, KellyC R (2006). AL-34662: a potent, selective, and efficacious ocularhypotensive serotonin-2 receptor agonist. J Ocul Pharmacol Ther.23:1-13].

Further, 5HT modulation can be useful in the treatment of pain, bothneuropathic and nociceptive pain, see for example U.S. Patentapplication publication US2007/0225277. Obata, Hideaki; Ito, Naomi;Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio Possible involvement ofspinal noradrenergic mechanisms in the antiallodynic effect ofintrathecally administered 5-HT2C receptor agonists in the rats withperipheral nerve injury. European Journal of Pharmacology (2007),567(1-2), 89-94. Serotonin2C receptor mRNA editing in neuropathic painmodel. Nakae, Aya; Nakai, Kunihiro; Tanaka, Tatsuya; Takashina, Masaki;Hagihira, Satoshi; Shibata, Masahiko; Ueda, Koichi; Mashimo, Takashi.Department of Anesthesiology & Intensive Care Medicine, Graduate Schoolof Medicine, Osaka University, Neuroscience Research (Amsterdam,Netherlands) (2008), 60(2), 228-231. Antiallodynic effects ofintrathecally administered 5-HT2C receptor agonists in rats with nerveinjury. Obata, Hideaki; Saito, Shigeru; Sakurazawa, Shinobu; Sasaki,Masayuki; Usui, Tadashi; Goto, Fumio Department of Anesthesiology, GunmaUniversity Graduate School of Medicine, Maebashi, Gunma, Japan. Pain(2004), 108(1-2), 163-169. Influence of 5,7-dihydroxytryptamine(5,7-DHT) on the antinociceptive effect of serotonin (5-HT) 5-HT2Creceptor agonist in male and female rats. Brus, Ryszard; Kasperska,Alicja; Oswiecimska, Joanna; Szkilnik, Ryszard. Department ofPharmacology, Silesian Medical University, Zabrze, Pol. Medical ScienceMonitor (1997), 3(5), 654-656.

Modulation of 5HT2 receptors may be beneficial in the treatment ofconditions related to bladder function, in particular, urinaryincontinence. [Discovery of a novel azepine series of potent andselective 5-HT2C agonists as potential treatments for urinaryincontinence. Brennan, Paul E.; Whitlock, Gavin A.; Ho, Danny K. H.;Conlon, Kelly; McMurray, Gordon. Bioorganic & Medicinal ChemistryLetters (2009), 19(17), 4999-5003. Investigation of the role of 5-HT2receptor subtypes in the control of the bladder and the urethra in theanesthetized female rat. Mbaki, Y.; Ramage, A. G. Department ofPharmacology, University College London, London, UK. British Journal ofPharmacology (2008), 155(3), 343-356.] In particular, compounds withagonist activity at 5-HT_(2C) have been shown to be useful in treatingurinary incontinence, see for example U.S. Patent applicationpublications US2008/0146583 and US 2007/0225274.

In the use and the method of the invention, an effective quantity of oneor more compounds, as a rule formulated in accordance withpharmaceutical and veterinary practice, is administered to theindividual to be treated, preferably a mammal, in particular a humanbeing, productive animal or domestic animal. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active compound(s) that is effective to achieve thedesired therapeutic response for a particular subject (e.g., a mammal,preferably, a human (patient)), compositions and mode of administration.The selected dosage level will depend upon the activity of theparticular compound, the route of administration, the severity of thecondition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

Compounds of the present invention can also be administered to a subjectas a pharmaceutical composition comprising the compounds of interest incombination with at least one pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of the presentinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa subject (namely, a mammal, such as a human) ranges from about 0.01mg/kg body weight to about 100 mg/kg body weight. More preferable dosescan be in the range of from about 0.01 mg/kg body weight to about 30mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration. Consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose.

In one aspect, the present invention provides pharmaceuticalcompositions. The pharmaceutical compositions of the present inventioncomprise the compounds of the present invention or an N-oxide, atautomeric form, a stereoisomer or a pharmaceutically acceptable salt orsolvate thereof. The pharmaceutical compositions of the presentinvention comprise compounds of the present invention that can beformulated together with at least one non-toxic pharmaceuticallyacceptable carrier.

In yet another embodiment, the present invention provides apharmaceutical composition comprising compounds of the present inventionor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, alone or in combination with one or more compounds that arenot the compounds of the present invention. Examples of one or morecompounds that can be combined with the compounds of the presentinvention in pharmaceutical compositions, include, but are not limitedto, one or more cognitive enhancing drugs.

The pharmaceutical compositions of this present invention can beadministered to a subject (e.g., a mammal, such as a human) orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of the present invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable nonirritating carriers or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of the presentinvention include powders, sprays, ointments and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich may be required. Ophthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.). Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,triethylammonium, diethylammonium, ethylammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The following examples serve to explain the invention without limitingit.

EXAMPLES

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz NMRinstrument (Bruker AVANCE), or by mass spectrometry, generally recordedvia HPLC-MS in a fast gradient on C18-material (electrospray-ionisation(ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet(m).

Enantiomers were separated/purified either by chiral supercritical fluidchromatography (SFC) (method A) or by chiral HPLC (method A).

Method A—Chiral Analytical SFC

Analytical SFC was performed on an Aurora A5 SFC Fusion and Agilent 1100system running under Agilent Chemstation software control. The SFCsystem included a 10-way column switcher, CO2 pump, modifier pump, oven,and backpressure regulator. The mobile phase comprised of supercriticalCO2 supplied by a beverage-grade CO2 cylinder with a modifier mixture ofmethanol at a flow rate of 3 mL/min. Oven temperature was at 35° C. andthe outlet pressure at 150 bar. The UV detector was set to collect atwavelengths of 220 nm and 254 nm. The mobile phase gradient started with5% modifier and held it for 0.1 minutes at a flow rate of 1 mL/min, thenthe flow rate was ramped up to 3 mL/min and held for 0.4 min. Themodifier was ramped from 5% to 15% over the next 8 minutes at 3 mL/minthen held for 1 minute at 15% modifier (3 mL/min) The gradient wasramped down from 15% to 5% modifier over 0.5 min (3 mL/min). Theinstrument was fitted with a Chiralpak AS-H column with dimensions of4.6 mm i d×150 mm length with 5 nm particles.

-   Method B—Chiral HPLC-   System: KNAUER preparative HPLC-   Pump: Preparative pump 1800-   Detector: Smartline UV detector 2600 257 nm-   Sample pump: Knauer HPLC-Pump K-120-   Fractional collector: Smartline Valves Drive S6-   Software: ChromGate® V3.1.7, KNAUER Instrument Control-   Column: Whelk O 4.6 mm ID×250 mm-   Column temperature: 25° C.-   Mobile phase: hexane/isopropylamine 95/5-   Flow rate: 1 ml/min    I. Preparation Examples

Example 1

8,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound of the formula I.g, I.h or I.i in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-1 of Table B)

1.1 Preparation of tert-butyl1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate

1 g (4.04 mmol) of tert-butyl2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was dissolved in20 mL of dichloromethane and treated with 1.54 mL (8.86 mL) oftriethylamine followed by 0.53 mL (4.83 mmol) of 3-methylbut-2-enoylchloride. The reaction mixture was stirred over night at roomtemperature, poured onto water (50 mL) and extracted three times with 50mL of dichloromethane each. The organic phases were combined, washedwith a saturated solution of sodium chloride, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica (eluent: 5-10% methanol in dichloromethane) toyield 1.27 g of the title compound as a white solid.

ESI-MS: m/z (%): 275 (80, [M-C₄H₉+2H]+, 331 (20, [M+H]⁺).

1.2 Preparation of tert-butyl8,8-dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 0.33 g (1.0 mmol) of tert-butyl1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylateof step 1.1 was irradiated with a 150 W mercury lamp in a immersion wellreactor with a pyrex filter in 20 mL of acetone until completion of thereaction monitored by liquid chromatography. The solution wasconcentrated in vacuo and the residue was purified by columnchromatography on silica (eluent: 10-30% ethyl acetate in heptane) toyield 202 mg of the title compound as a beige solid.

ESI-MS: m/z (%): 275 (80, [M-C₄H₉+2H]⁺, 331 (20, [M+H]⁺).

1.3 Preparation of tert-butyl8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 38 mg (0.115 mmol) tert-butyl8,8-dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylateof step 1.2 in 1 mL of tetrahydrofuran was treated with 0.46 mL of 1molar solution of borohydride-tetrahydrofuran complex intetrahydrofuran. The mixture was stirred over night, and then quenchedwith water and diluted hydrochloric acid. The pH was adjusted to pH 9 byaddition of aqueous sodium hydroxide solution and the mixture extractedthree times with 10 mL of dichloromethane each. The solution was driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica (eluent: 20-30% ethylacetate in heptane) to yield 21 mg of the title compound as a clear oil.

ESI-MS: m/z (%): 317 (100, [M+H]⁺).

1.4 Preparation of8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

287 mg (0.9 mmol) of tert-butyl8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylateof step 1.3 were dissolved in 5 mL of dichloromethane and treated with2.5 mL of trifluoroacetic acid. The mixture was stirred over night atroom temperature and then extracted once with water (10 mL). The organicphase was then extracted twice with a diluted solution of sodiumhydroxide (10 mL each), dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on silica(eluent: 10-30% methanol in dichloromethane) to yield 141 mg of thetitle compound as a yellow oil.

ESI-MS: m/z (%): 217.15 (100, [M+H]⁺).

¹H-NMR (500 MHz, CDCl₃): δ=7.15 (d, 1H), 6.85 (d, 1H), 6.75 (m, 1H),3.80 (s, 2H), 3.15 (m, 2H), 3.00 (s, 4H), 1.65 (m, 2H), 1.20 (s, 6H).

Example 2

1,2,3,4-Tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclopent[2]en]-6(7H)-one2,2,2-trifluoroacetate (compound of the formula I.j, I.k or I.l in whichthe combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-401of Table B)

2.1 Preparation of tert-butyl6-oxo-3,4,6,7-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclopent[2]ene]-2(1H)-carboxylate(compound of the formula I.g, I.h or I.i in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-401 of Table B, whereinhowever R¹ is not H, but Boc)

A solution of 50 mg (0.128 mmol) tert-butyl9-chloro-1-(2-cyclopentenylacetyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylatewas dissolved in 1 mL of degassed dry acetonitrile under argon, treatedwith 1.4 mg (0.006 mmol) of palladium acetate, 6.10 mg (0.013 mmol)dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine and 53 mg(0.384 mmol) potassium carbonate. The mixture was stirred for 10 hoursat 120° C. in a synthesis microwave system. After cooling to roomtemperature the mixture was filtered over celite, diluted withdichloromethane and then extracted twice with a diluted solution ofsodium chloride (10 mL each), dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica (eluent: 10-30% ethyl acetate in heptane) to yield 40 mg ofthe title compound as a yellow oil.

ESI-MS: m/z (%): 298 (80, [M-C₄H₉+2H]⁺, 217 (20, [M+H]⁺).

2.2 Preparation of1,2,3,4-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclopent[2]en]-6(7H)-one2,2,2-trifluoroacetate

Boc-deprotection of the compound obtained in step 2.1 analogously toexample 1.4 yielded the title compound.

ESI-MS: m/z (%): 255 (100, [M+I-1]⁺).

Example 3

8-Methyl-8-phenyl-3,4,7,8-tetrahydro-1H-[1,4] diazepino[6,7,1-ij] quinolin-6(2H)-one, hydrochloride (compound of the formula I.j, I.k or I.l inwhich the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in rowB-161 of Table B)

392 mg (1 mmol) of tert-butyl1-(3-phenylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylatewere treated with 1 g of polyphosphoric acid. The mixture was heated to90° C. for 2 hours and then quenched with a saturated solution ofpotassium carbonate at 0° C. The mixture was extracted three times withethyl acetate (20 mL each), the combined organic fractions dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica (eluent: 10-30% methanol indichloromethane) to yield 86 mg of the title compound as a yellow foam.

ESI-MS: m/z (%): 293.1 (100, [M+H]⁺).

1H-NMR (500 MHz, DMSO-d6): δ=10.05 (bs, 1H), 9.85 (bs, 1H), 7.40 (d,1H), 7.35 (d, 1H), 7.25 (m, 2H), 7.20 (m, 2H), 7.10 (m, 2H), 4.55 (m,1H), 4.35 (m, 1H), 4.15 (m, 1H), 3.55 (m, 1H), 3.25 (m, 2H), 3.10 (m,1H), 2.70 (m, 1H), 1.60 (s, 3H).

The following example was prepared analogously to example 1.

Example 4

8,8-Dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6(2H)-one(compound of the formula I.j, I.k or I.l in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-1 of Table B)

ESI-MS: m/z (%): 231 (100, [M+H]⁺).

1H-NMR (500 MHz, CDCl₃): δ=7.20 (d, 1H), 7.00 (m, 2H), 4.10 (s, 4H),3.20 (m, 2H), 2.50 (s, 2H), 1.30 (s, 6H).

The following examples 5 and 6 were prepared analogously to example 2.

Example 5

1,2,3,4-Tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclopentan]-6(7H)-one (compoundof the formula I.j, I.k or I.l in which the combination of R^(5a),R^(5b), R⁷, R⁸ and R^(9a) is as in row B-281 of Table B)

ESI-MS: m/z (%): 257 (100, [M+H]⁺).

Example 6

1,2,3,4,6,7-Hexahydrospiro [ [1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclopentane] (compound of the formulaI.g, I.h or I.i in which the combination of R^(5a), R^(5b), R⁷, R⁸ andR^(9a) is as in row B-281 of Table B)

ESI-MS: m/z (%): 243 (100, [M+H]⁺).

¹H-NMR (500 MHz, CDCl₃): δ=7.15 (d, 1H), 6.95 (d, 1H), 6.80 (m, 1H),3.90 (s, 2H), 3.20 (m, 2H), 3.05 (m, 4H), 1.95-1.65 (m, 10H).

The following examples 7 to 13 were prepared analogously to example 1.

Example 7

12a-Methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinolin-9(9aH)-one (racemic cis diastereomer of thecompound of the formula I.j, I.k or I.l in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-441 of Table B)

ESI-MS: m/z (%): 257 (100, [M+H]⁺).

Example 8

8-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(single enantiomer of the compound of the formula I.g, I.h or I.i inwhich the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in rowB-81 of Table B)

ESI-MS: m/z (%): 271 (100, [M+H]⁺).

The retention time according to method A is 1.396 min.

Example 9

8-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(single enantiomer of the compound of the formula I.g, I.h or I.i inwhich the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in rowB-81 of Table B)

ESI-MS: m/z (%): 271 (100, [M+H]⁺).

The retention time according to method A is 1.396 min is 1.543 min.

Example 10

12a-Methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinolin-9(9aH)-one (racemic trans diastereomer ofthe compound of the formula I.j, I.k or I.l in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-441 of Table B)

ESI-MS: m/z (%): 257 (100, [M+H]⁺).

Example 11

12a-Methyl-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino[6,7,1-ij]quinoline(racemic cis diastereomer of the compound of the formula I.g, I.h or I.iin which the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as inrow B-441 of Table B)

ESI-MS: m/z (%): 243 (100, [M+H]⁺).

¹H-NMR (500 MHz, CDCl₃): δ=7.15 (d, 1H), 6.90 (d, 1H), 6.80 (m, 1H),3.90 (m, 2H), 3.15 (m, 1H), 3.05 (m, 3H), 2.95 (m, 1H), 2.80 (m, 1H),1.95 (m, 1H), 1.90 (m, 1H), 1.80 (m, 2H), 1.60 (m, 1H), 1.55 (m, 1H),1.30 (m, 1H), 1.20 (s, 3H).

Example 12

8-Methyl-8-(trifluoromethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6(2H)-one(racemic mixture of compound of the formula I.j, I.k or I.l in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-81 ofTable B)

ESI-MS: m/z (%): 285 (100, [M+H]⁺).

Example 13

12a-Methyl-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino-[6,7,1-ij]quinolinehydrochloride (racemic trans diastereomer of the compound of the formulaI.g, I.h or I.i in which the combination of R^(5a), R^(5b), R⁷, R⁸ andR^(9a) is as in row B-441 of Table B)

ESI-MS: m/z (%): 243 (100, [M+H]⁺).

¹H-NMR (500 MHz, CDCl₃): δ=9.45 (bs, 1H), 9.05 (bs, 1H), 7.05 (d, 1H),7.00 (d, 1H), 6.70 (m, 1H), 4.30 (m, 1H), 3.95 (m, 1H), 3.55 (m, 2H),3.35 (m, 1H), 3.25 (m, 2H), 2.95 (m, 1H), 1.95 (m, 1H), 1.85 (m, 1H),1.80 (m, 1H), 1.70 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.25 (m, 1H),0.90 (s, 3H).

The following examples 14 and 15 were prepared analogously to example 3.

Example 14

8-Methyl-8-phenyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolinedihydrochloride (racemic mixture in form of the salt of the compound ofthe formula I.g, I.h or I.i in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) is as in row B-161 of Table B)

ESI-MS: m/z (%): 279 (100, [M+H]⁺)

¹H-NMR (500 MHz, CDCl₃): δ=7.22-7.27 (m, 2H), 7.11-7.19 (m, 3H),6.95-7.04 (m, 2H), 6.78 (dd, J=8.0, 7.5 Hz, 1H), 3.99 (d, J=14.4 Hz,1H), 3.87 99 (d, J=14.5 Hz, 1H), 3.20-3.26 (m, 1H), 3.01-3.08 (m, 4H),2.87-2.94 (m, 1H), 2.09-2.15 (m, 1H), 1.92-1.99 (m, 1H), 1.73 (s, 3H)ppm.

Example 15

8-Methyl-8-phenyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline,bis hydrochloride (racemic mixture of compound of the formula I.g, I.hor I.i in which the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) isas in row B-161 of Table B)

ESI-MS: m/z (%): 279 (100, [M+H]⁺).

¹H NMR (CDCl₃, 500 MHz): [ppm]: 7.25 (m, 2H), 7.15 (m, 3H), 7.05 (d,1H), 6.95 (d, 1H), 6.80 (m, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 3.25 (m,1H), 3.05 (m, 4H), 2.90 (m, 1H), 2.10 (m, 1H), 1.95 (m, 1H), 1.75 (s,3H).

Example 16

(R)-5,6,7,9,9a,10,11,12-Octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxalinebis(2,2,2-trifluoroacetate) (R-enantiomer of the compound of the formulaI.a, I.b or I.c in which the combination of R^(5a), R^(5b), R⁷, R⁸ andR^(9a) is as in row A-121 of Table A)

16.1 Preparation of (R)-tert-butyl9-oxo-6,7,9a,10,11,12-hexahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline-5(9H)-carboxylate

65 mg of (R)-tert-butyl9-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylatewas stirred together with 1.8 mg of2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2.5 mgPd₂(dba)₃ and 19 mg sodium 2-methylpropan-2-olate at 100° C. over 10hours in toluene. The reaction mixture was then cooled to roomtemperature and evaporated. The residue was purified by columnchromatography on silica (eluent: 10-25% ethyl acetate in heptane) toyield 20 mg of the title compound as a beige solid.

ESI-MS: m/z (%): 288 (80, [M-C₄H₉+2H]⁺, 344 (20, [M+H]⁺).

16.2 Preparation of (R)-tert-butyl6,7,9a,10,11,12-hexahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline-5(9H)-carboxylate(R-enantiomer of the compound of the formula I.a, I.b or I.c in whichthe combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row A-121of Table A, wherein however R¹ is not H, but Boc)

Reduction of the compound obtained in step 16.1 analogously to example1.3 yielded the title compound.

ESI-MS: m/z (%):274 (80, [M-C₄H₉+2H]⁺, 330 (20, [M+H]⁺).

16.3 Preparation of(R)-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxalinebis(2,2,2-trifluoroacetate) (R-enantiomer of the compound of the formulaI.a, I.b or I.c in which the combination of R^(5a), R^(5b), R⁷, R⁸ andR^(9a) is as in row A-121 of Table A)

Boc-deprotection of the compound obtained in step 2.1 analogously toexample 1.4 yielded the title compound.

ESI-MS: m/z (%): 230 (100, [M+H]⁺).

Example 17 was prepared analogously to example 16 employing(S)-tert-butyl9-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylateas starting material which was derived from(R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid.

Example 17

(S)-5,6,7,9,9a,10,11,12-Octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline bis(2,2,2-trifluoroacetate)(S-enantiomer of the compound of the formula I.a, I.b or I.c in whichthe combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row A-121of Table A)

ESI-MS: m/z (%): 230 (100, [M+H]⁺).

The following examples 18 to 23 were prepared analogously to example 1.

Example 18

9-Chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolinebis(2,2,2-trifluoroacetate) (compound of the formula I.g in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-3 ofTable B)

ESI-MS: m/z (%): 251 (100, [M+H]⁺).

Example 19

10-Chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline bis(2,2,2-trifluoroacetate) (compound of the formula I.h inwhich the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in rowB-3 of Table B)

ESI-MS: m/z (%): 251 (100, [M+H]⁺).

Example 20

9-Chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6(2H)-one2,2,2-trifluoroacetate (compound of the formula I.j in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-3 ofTable B)

ESI-MS: m/z (%): 265 (100, [M+H]⁺).

Example 21

10-Chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6(2H)-one2,2,2-trifluoroacetate (compound of the formula I.k in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-3 ofTable B)

ESI-MS: m/z (%): 265 (100, [M+H]⁺).

Example 22

9-Fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(compound of the formula I.g in which the combination of R^(5a), R^(5b),R⁷, R⁸ and R^(9a) is as in row B-2 of Table B)

ESI-MS: m/z (%): 235 (100, [M+H]⁺).

Example 23

10-Fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolinebis(2,2,2-trifluoroacetate) (compound of the formula I.h in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-2 ofTable B)

ESI-MS: m/z (%): 235 (100, [M+H]⁺).

The following examples 24 to 26 were prepared analogously to example 2.

Example 24

1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclohexane](2,2,2-trifluoroacetate) (compound of the formula I.g, I.h or I.i inwhich the combination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in rowB-321 of Table B)

ESI-MS: m/z (%): 257.2 (100, [M+H]⁺).

¹H NMR (CDCl₃, 500 MHz): [ppm]: 8.85 (bs, 2H), 7.45 (d, 1H), 7.15 (d,1H), 6.90 (m, 1H), 4.15 (s, 2H), 3.25 (m, 4H), 3.15 (m, 2H), 1.80 (m,2H), 1.70 (m, 4H), 1.55 (m, 4H), 1.30 (m, 2H).

Example 25

1′,2′,3′,4′,6′,7′-Hexahydrospiro[cyclobutane-1,8′-[1,4]diazepino[6,7,1-ij]quinoline],hydrochloride (compound of the formula I.g, I.h or I.i in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-241 ofTable B)

ESI-MS [M+H+]=229.20

¹H NMR (CDCl₃, 500 MHz): [ppm]: 8.80 (bs, 2H), 7.50 (d, 1H), 6.95 (d,1H), 6.90 (m, 1H), 4.10 (s, 2H), 3.25 (m, 2H), 3.20 (m, 2H), 3.10 (m,2H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (m, 4H).

Example 26

9′-Fluoro-1′,2′,3′,4′,6′,7′-hexahydrospiro[cyclobutane-1,8′-[1,4]diazepino[6,7,1-ij]quinoline],hydrochloride (compound of the formula I.g in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-242 of Table B)

ESI-MS [M+H+]=247.15

¹H NMR (DMSO-d₆, 500 MHz): [ppm]: 9.00 (bs, 2H), 7.25 (m, 1H), 6.80 (m,1H), 4.10 (s, 2H), 3.25 (m, 2H), 3.20 (m, 2H), 3.10 (m, 2H), 2.65 (m,2H), 2.00 (m, 4H), 1.85 (m, 2H).

The following examples 27 and 28 were prepared analogously to example 1.

Example 27

Enantiomer of7,8,8-trimethyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinoline](enantiomer of the compound of the formula I.g, I.h or I.i in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-25 ofTable B)

ESI-MS [M+H+]=231.20

¹H NMR (CDCl3, 500 MHz): [ppm]: 7.25 (d, 1H), 7.00 (d, 1H), 6.85 (dd,2H), 4.00 (m, 1H), 3.90 (m, 1H), 3.15 (m, 4H), 3.05 (m, 2H), 1.85 (m,1H), 1.30 (s, 3H), 1.10 (s, 3H), 0.95 (d, 3H).

The retention time of the Boc-protected precursor according to method Bis 10.363.

Example 28

Enantiomer of7,8,8-trimethyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinoline](enantiomer of the compound of the formula I.g, I.h or I.i in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-25 ofTable B)

ESI-MS [M+H+]=231.20

¹H NMR (CDCl3, 500 MHz): [ppm]: 7.25 (d, 1H), 7.00 (d, 1H), 6.85 (dd,2H), 4.00 (m, 1H), 3.90 (m, 1H), 3.15 (m, 4H), 3.05 (m, 2H), 1.85 (m,1H), 1.30 (s, 3H), 1.10 (s, 3H), 0.95 (d, 3H).

The retention time of the Boc-protected precursor according to method Bis 11.410 min.

The following example 29 was prepared analogously to example 2.

Example 29

3-Methyl-1′,2′,3‘,4’,6′,7′-hexahydrospiro[cyclobutane-1,8′-[1,4]diazepino[6,7,1-ij]quinoline],hydrochloride (compound of the formula I.p, I.q or I.r in which thecombination of R^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row B-241 ofTable B)

ESI-MS [M+H+]=243.20

¹H NMR (DMSO-d₆, 500 MHz): [ppm]: 9.30 (bs, 2H), 8.55 (bs, 1H), 7.60 (d,1H), 7.20 (d, 1H), 6.95 (dd, 1H), 4.20 (m, 1H), 4.05 (m, 1H), 3.35 (m,1H), 3.20 (m, 2H), 2.90 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 2.05 (m,1H), 1.95 (m, 6H), 1.2 (d, 3H).

Example 30

3-Benzyl-2′,3′,7′,8′,9′,10′-hexahydro-1H-3′,8′,10a′-triaza-cyclohepta[de]naphthalene(compound of the formula I.a, I.b or I.c in which the combination ofR^(5a), R^(5b), R⁷, R⁸ and R^(9a) is as in row A-121 of Table A)

30.1 Preparation of2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-acetamide

A solution of 1 g (4.46 mmol) 1-benzyl-1,2,3,4-tetrahydroquinoxaline in10 ml of dimethylformamide was treated with 3.14 ml (18.15 mmol) ofN-Ethyl-N-isopropylpropan-2-amine, and subsequently 863 mg (9.23 mmol)2-chloroacetamide was added. The reaction mixture was heated in amicrowave system at 100° C. for four hours. The resulting mixture wasquenched with water and extracted once with ethylacetate. The aqueousphase was set to pH 10 with sodium hydroxide solution and extracted 3×with ethylacetate. The combined organic extracts were dried withmagnesium sulfate, evaporated till dryness and directly purified bycolumn chromatography on silica (eluent: starting with heptane and thenup to 100% ethylacetate) to yield 1.224 g of the title compound.

ESI-MS: m/z (%): 282.10 (100, [M+H]+).

30.2 Preparation of2-(4-Benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-ethylamine

To 1.224 g (4.35 mmol) of2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-acetamide were added 10.88ml (21.75 mmol) borane dimethylsulfide THF solution and subsequentlyheated to 60° C. for six hours in a microwave system. The mixture wasquenched with 1 molar hydrochloric acid and methanol and heated for 15minutes at 60° C. in a microwave system. The reaction mixture wasdiluted with ethylacetate and extracted 3× with 1 molar hydrochloridacid. The combined aqueous phases were set to pH 10 with sodiumhydroxide solution and extracted 3× with dichloromethane. The combinedorganic phases were dried and evaporated to yield 1.089 g of the titlecompound as an oil.

ESI-MS: m/z (%): 268.15 (100, [M+H]+).

30.3 Preparation of3-benzyl-2,3,7,8,9,10-hexahydro-1H-3,8,10a-triaza-cyclohepta[de]-naphthalene

A solution of 1.089 g (4.07 mmol) of2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-ethylamine and 20 ml ethanolwas treated with 122 mg (4.07 mmol) of formaldehyde and 511 mg (4.48mmol) of trifluoroacetic acid and stirred over night at roomtemperature. The solvent was evaporated and dichloromethane was added tothe crude mixture. The organic phase was washed with 1 molar sodiumhydroxide solution. The organic phase was dried and purified by columnchromatography on silica (eluent: starting with dichloromethane and thenup to 100% methanol) to yield 448 mg of the title compound.

ESI-MS [M+H+]=280.10 (100, [M+H]+).

¹H NMR (CDCl3, 500 MHz): [ppm]: 7.35 (m, 3H), 7.30 (m, 2H), 6.80 (dd,1H), 6.65 (d, 1H), 6.60 (d, 1H), 4.55 (s, 2H), 4.10 (s, 2H), 3.30 (m,4H), 3.25 (m, 2H), 3.10 (m, 2H).

Example 31

9-Fluoro-1-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclobutane], trifluoroacetic acidsalt (compound of the formula I.m in which the combination of R^(5a),R^(5b), R⁷, R⁸ and R^(9a) is as in row B-242 of Table B)

31.1 Preparation of 2-cyclobutylidene-N-(3-fluorophenyl)-acetamide

1.5 g (13.50 mmol) of 3-fluoroaniline were dissolved in 20 ml ofdichloromethane and treated with 5.19 g (29.7 mmol) ofN-ethyl-N-isopropylpropan-2-amine. Within 10 min 12.82 g (16.20 mmol) of2-cyclobutylideneacetyl chloride were added at 0° C. and the solutionwas stirred overnight at room temperature. The mixture was poured on icewater and extracted 2x with dichloromethane. The combined organic phaseswere washed once with saturated sodium chloride solution, dried withMgSO₄ and evaporated in vacuo. The crude oil was treated with heptaneand decanted twice, redissolved in ether-dichloromethane and treatedwith heptane till crystallization, yielding 2.2 g (77%) of a beigesolid.

ESI-MS: m/z (%): 206 (100, [M+H]+).

31.2 Preparation of5′-fluoro-1′H-spiro[cyclobutane-1,4′-quinolin]-2′(3′H)-one

A solution of 400 mg (1.94 mmol) of2-cyclobutylidene-N-(3-fluorophenyl)-acetamide obtained in step 31.1 wasdissolved in 19.5 ml of toluene and irradiated with a Hg middle pressurelamp in a suitable device till completion of the reaction indicated byliquid chromatography. The crude solution was concentrated in vacuo andthe residue was purified by column chromatography on silica (eluent:10-30% ethyl acetate in heptane) to yield 55 mg (14%) of the titlecompound as a beige solid.

ESI-MS: m/z (%): 206 (100, [M+H]+).

31.3 Preparation of5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinoline]

A solution of 50 mg (0.244 mmol) of5′-fluoro-1′H-spiro[cyclobutane-1,4′-quinolin]-2′(3′H)-one obtained instep 31.2 in 1 mL of tetrahydrofuran was treated with 0.73 mL of 1 Msolution of borohydride-tetrahydrofuran complex in tetrahydrofuran. Themixture was stirred at reflux for 2 h, quenched with water andevaporated till dryness. The crude compound was used in the subsequentstep without purification.

ESI-MS: m/z (%): 192 (100, [M+H]+).

31.4 Preparation of2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)-acetamide

A solution of 50 mg (0.26 mmol) of5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinoline] obtainedin step 31.3 in 1 ml of dimethylformamide was treated with 6.2 mg (0.26mmol) of sodium hydride followed by 72 mg (0.52 mmol) 2-bromoacetamideand heated in a microwave system at 100 C for one hour. The resultingmixture was quenched with water, evaporated till dryness and directlypurified by column chromatography on silica (eluent: 10% methanol indichloromethane) to yield 70 mg of the title compound with about 80%purity determined by LCMS.

ESI-MS: m/z (%): 249 (100, [M+H]+).

31.5 Preparation of2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)ethanamine

A solution of 40 mg (0.16 mmol) of2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)-acetamideobtained in step 31.4 in 1 ml of tetrahydrofurane was treated with 38 μl(0.40 mmol) of borane dimethylsulfide and heated to 70° C. for twohours. The mixture was quenched with water and hydrochloric acid,diluted with dichloromethane and extracted twice with water. Thecombined aqueous phases were set to pH 10 with sodium hydroxide solutionand extracted 3x with dichloromethane. The combined organic phases weredried and evaporated to yield 10 mg of the title compound as an oil.

ESI-MS: m/z (%): 235 (100, [M+H]+).

31.6 Preparation of9-fluoro-1-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1′-cyclobutane],trifluoroacetic acid salt

A solution of 10 mg (0.043 mmol) of2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)ethan-amineobtained in step 31.5 in 0.4 ml of acetonitrile/methanol was treatedwith 3.8 mg (0.085 mmol) of acetaldehyde and 6.5 μl (0.085 mmol) oftrifluoroacetic acid and stirred over night at room temperature. Thesolvent was evaporated and the crude mixture purified with reversedphase liquid chromatography to yield 1.5 mg of the title compound asbeige solid.

ESI-MS: m/z (%): 261 (100, [M+H]+).

¹H-NMR (500 MHz, pyridine-d5): δ=7.06 (dd, J=8.3, 6.4 Hz, 1H), 6.79 (dd,J=11.8, 8.4 Hz, 1H), 4.18 (q, J=6.9, 13.8 Hz, 1H), 3.10-3.00 (m, 2H),2.99-2.95 (m, 2H), 2.85-2.80 (m, 2H), 2.79-2.70 (m, 2H), 2.09-1.97 (m,2H), 1.90-1.70 (m, 4H), 1.51 (d, J=6.9, 3H) ppm.

II. BIOLOGICAL TESTS

Functional Activity

The functional activity of compounds of formula I was assayed byincubation with U2OS_HTR_(2C) _(_)β-Arrestin cells (DiscoverX,93-0289C3) to induce beta-arrestin2 recruitment to the 5-HT_(2C)receptor. The agonist-induced recruitment and proximity of the receptorand beta-arrestin2 leads to complementation and formation of activeβ-galactosidase. The enzyme complementation results in enzyme activity,which is measured following the termination of the agonist incubationusing DiscoveRx's detection reagent, which contains a chemiluminescentsubstrate which produces a high intensity signal. Cells were plated anda medium-change to a 1% serum containing medium was performed 24 hlater. The next day, test compounds were added and incubated for 1.5 hbefore addition of detection reagent.

The response produced was measured and compared with the responseproduced by 10 [mu]M 5-HT or the maximal effect induced by 5-HT (definedas 100%) to which it was expressed as a percentage response (relativeefficacy). Dose response curves were constructed using Graphpad Prism(Graph Software Inc.) or using in house adapted software using a 4parameter dose response model with variable slope(fit=(Bottom+(Top-Bottom)/(1+10^((Log EC50−x)*HillSlope))res=(y-fit)).Results are compiled in the table below.

TABLE Potency (EC50) in # functional assay % efficacy 1 ++ 71 6 ++ 63 8++ 40 9 +++ 61 16 + 55 17 ++ 84 19 ++ 25 22 ++ 69 25 ++ 90 26 +++ 10727 + 87 28 ++ 55 Potency (EC50): + from 200 nM to <1 μM ++ from 20 nM to<200 nM +++ <20 nM

We claim:
 1. A compound of the formula I

wherein G is (CR^(3a)R^(3b))_(n); X is NR⁶ ; R¹ is selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic moieties in the three last-mentioned radicals may be substituted with one or more substituents R¹¹; each R² is independently selected from the group consisting of cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹¹; R^(3a) and R^(3b), independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, and fluorinated C₁-C₆-alkyl; R^(4a) and R^(4b), independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆ alkoxy C₁-C₄-alkyl C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰, —C(O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹¹; or  R^(4a) and R^(4b) form together a group ═O or ═S; R^(5a) and R^(5b), independently of each other, are selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from from the group consisting of N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹¹; or R^(5a) and R⁶, together with the atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹¹; R⁶ is selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —C(═O)R¹⁰, —SO₂R¹⁰, phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic moieties in the three last-mentioned radicals may be substituted with one or more substituents R¹¹; each R⁹ is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), —NR^(12a)C(O)R¹⁰, —C(═O)R¹⁰, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹¹; each R¹⁰ is independently selected from the group consisting of hydrogen, cyano, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the five last-mentioned radicals may be substituted with one or more substituents R¹¹; each R¹¹ is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —COOH, —NR^(12a)R^(12b), —CH₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, SO₂NR^(12a)R^(12b), C₁-C₆-alkylcarbonyloxy and fluorinated C₁-C₆-alkylcarbonyloxy; R^(12a) and R^(12b), independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from the group consisting of halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,  if R^(12a) and R^(12b) are bound to the same nitrogen atom, together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents selected from the group consisting of halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; a is 0, 1 or 2; b is 0, 1, 2 or 3; and n is 1; or pharmaceutically acceptable salt thereof, or the compound of the general formula I, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.
 2. The compound as claimed in claim 1, wherein at least one hydrogen atom has been replaced by a deuterium atom.
 3. The compound as claimed in claim 1, where R¹ is hydrogen or C₁-C₆-alkyl.
 4. The compound as claimed in claim 1, where R² is selected from the group consisting of cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy.
 5. The compound as claimed in claim 1, Where R^(3a) and R^(3b), independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy.
 6. The compound as claimed in claim 5, where R^(3a) is selected from the group consisting of hydrogen, cyano, nitro, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy, and R^(3b) is hydrogen.
 7. The compound as claimed in claim 6, where R^(3a) is hydrogen or methyl, and R^(3b) is hydrogen.
 8. The compound as claimed in claim 7, where R^(3a) and R^(3b) are hydrogen.
 9. The compound as claimed in claim 1, where R^(4a) and R^(4b) , independently of each other, are selected from the group consisting of hydrogen, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl or form together a group ═O.
 10. The compound as claimed in claim 1, where R^(5a) is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or R^(5a) and R⁶, together with the atoms they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹¹; and R^(5b) is hydrogen or deuterium.
 11. The compound as claimed in claim 10, where R^(5a) is selected from the group consisting of hydrogen, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl; or  R^(5a) and R⁶ form together a group (CH₂)_(r),where r is 2, 3, 4 or 5; and R^(5b) is hydrogen or deuterium.
 12. The compound as claimed in claim 1, where R⁶ is —SO₂R¹⁰.
 13. The compound as claimed in claim 12, Where R¹⁰ is selected from the group consisting of C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and phenyl, where phenyl may be substituted with 1, 2, 3, 4 or 5 radicals R¹¹.
 14. The compound as claimed in claim 1, where R⁶ is selected from the group consisting of C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing , 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic moieties in the three last-mentioned radicals may be substituted with one or more substituents R¹¹.
 15. The compound as claimed in claim 1, where R^(5a) and R⁶, together with the atoms they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹¹.
 16. The compound as claimed in claim 15, where R^(5a) and R⁶ form together a group (CH₂)_(r), where r is 2, 3, 4 or
 5. 17. The compound as claimed in claim 1, where each R⁹ is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl fluorinated C₁-C₆-alkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy and a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO and SO₂ as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹¹.
 18. The compound as claimed in claim 1, where each R¹¹ is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy.
 19. The compound as claimed in claim 1, where a is 0 or
 1. 20. The compound as claimed in claim 1, where b is 0 or
 1. 21. The compound as claimed in claim 1, of formula (I.1)


22. The compound as claimed in claim 21, of formula (I.1.1)

wherein R ^(9a) is H or F b=1, 2 or
 3. 23. The compound as claimed in claim 1, of formula(I.2)

wherein R^(2a) and R^(2b) are independently hydrogen or methyl.
 24. The compound as claimed in claim 23, of formula (I.2.1)

wherein R^(9a) is H or F; R^(2a) and R^(2b) are independently hydrogen or methyl; and b=1, 2 or
 3. 25. The compound as claimed in claim 3, where R¹ is hydrogen.
 26. The compound as claimed in claim 4, where R² is C₁-C₆-alkyl.
 27. The compound as claimed in claim 9, where R^(4a) and R^(4b) are hydrogen of form together a group ═O.
 28. The compound as claimed in claim 27, where R^(4a) and R^(4b) are hydrogen. 